Pharmacokinetic herb-drug interactions (part 2): Drug interactions involving popular botanical dietary supplements and their clinical relevance
Open accessAbstract
In Part 2 of this review, a critical examination of the pertinent scientific literature is undertaken in order to assess the interaction risk that popular dietary supplements may pose when taken concomitantly with conventional medications. Botanicals most likely to produce clinically important herb-drug interactions are those whose phytochemicals act as mechanism-based inhibitors of cytochrome P450 enzyme activity (e.g., Hydrastis canadensis, Piper nigrum, Schisandra chinensis ) or function as ligands for orphan nuclear receptors (e.g., Hypericum perforatum ). In addition, several external factors unrelated to phytochemical pharmacology can augment the drug interaction potential of botanical supplements. Key Words herb-drug interaction - plant secondary metabolites - cytochrome P450 enzymes - transferases - ATP-binding cassette transporters - solute carrier membrane transport proteins - botanical dietary supplements - black cohosh - Echinacea - garlic - Ginkgo biloba - ginseng - goldenseal - kava - black pepper - piperine - Schisandra - milk thistle - St. John's wort - methylenedioxyphenyl-containing compounds
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Written from the paper’s full text.
TL;DR
This review critically assesses clinical evidence for herb-drug interactions of popular botanical supplements, concluding most pose low risk at recommended doses while goldenseal, black pepper/piperine, Schisandra, and St. John’s wort pose high risk. Risk is driven mainly by mechanism-based CYP inhibition from methylenedioxyphenyl phytochemicals or nuclear receptor activation by hyperforin/PXR.
Key findings
- Black cohosh, Echinacea, garlic, ginkgo at ≤240 mg/day, ginseng, kava, and milk thistle were rated low interaction risk; goldenseal, black pepper/piperine, Schisandra, and St. John’s wort were rated high risk.
- Goldenseal: 14 days of supplementation (~209 mg isoquinoline alkaloids daily) significantly increased midazolam AUC, Cmax, and elimination half-life, with effects proportional to clarithromycin 1000 mg daily; hydrastine inhibited CYP3A4 with IC50 = 25 µM versus berberine IC50 = 400 µM.
- Black pepper/piperine: every prospective human trial showed improved oral bioavailability, with mean AUC increases of phenytoin 16–133%, rifampicin 69%, propranolol 103%, theophylline 96%, and nevirapine 170%; concern is greatest with CYP3A and/or ABCB1 substrates and piperine/piperamides >10 mg.
- St. John’s wort: hyperforin is a potent PXR activator with EC50 = 23 nM, below usual human plasma concentrations of ~100–300 nM; >70% of prescription medications are susceptible, and extracts with <1% hyperforin are less likely to produce clinically relevant interactions.
- Schisandra: clinical AUC increases were 1.5-fold for talinolol, 2.1-fold for tacrolimus, and 2.0-fold for midazolam; gomisins B, C, and G inhibited human CYP3A4 with IC50 values <1.5 µM.
- Ginkgo: among 29 prospective clinical trials, 23 observed no significant effects on drug disposition, 5 observed modest inhibition, and 3 showed evidence of CYP3A4, CYP2C9, or CYP2C19 induction; doses >240 mg/day may increase interaction prospects.
- Garlic: garlic oil inhibited human CYP2E1 by almost 40% in young adults and 25% in elderly adults; garlic powder reduced saquinavir mean AUC, 8-hour trough concentrations, and Cmax by 50%; a standardized garlic extract increased duodenal ABCB1 expression by 31%.
- Milk thistle: standard extracts had no observable effects on many drugs; silymarin increased talinolol AUC by 36% and reduced metronidazole AUC by 29%; in CYP2C9*1/*1 subjects, silymarin produced a 2-fold increase in losartan AUC and Cmax, but not in CYP2C9*1/*3 subjects.
Methods
- Narrative critical review of published clinical and nonclinical literature on selected popular botanical dietary supplements, presented as Part 2 of a two-part review.
- For each botanical, the paper assesses in vitro, animal, and human pharmacokinetic interaction data, focusing on cytochrome P450 enzymes, transferases, ABC transporters, and solute carrier transporters, and assigns a qualitative interaction risk rating.
- No new primary data are reported; no systematic search strategy or meta-analysis is described.
Limitations
- The paper states that phytochemical profiles and label claims for “standardized” botanical products can vary considerably, which can affect interpretation of efficacy and herb-drug interaction studies.
- The paper states that most botanicals have not been evaluated clinically and that no clinical assessments of botanical extracts using novel bioavailability-enhancing formulations have been reported.
- The paper notes methodological concerns in specific studies, such as the Yuan et al. ginseng-warfarin trial being underpowered, using inadequate sampling for AUC, and using a non-stereoselective assay; evident from the text, the review’s risk ratings are qualitative and not based on formal meta-analysis.
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Cites
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Claims the paper makes
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- Findingcitation
St. John's wort decreases plasma levels of quazepam in humans.
“| Quazepam | decrease plasma level of drug | [403] |”
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St. John's wort decreases plasma levels of simvastatin in humans.
“| Simvastatin | decrease plasma level of drug | [398] |”
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St. John's wort decreases plasma levels of amitriptyline in humans.
“| Amitriptyline | decrease plasma level of drug | [391] |”
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St. John's wort decreases plasma levels of midazolam in humans.
“| Midazolam | decrease plasma level of drug | [90, 98, 384, 386, |”
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St. John's wort has a mixed effect on fexofenadine plasma levels, generally decreasing them in humans.
“| Fexofenadine | mixed, generally decreases | [395-397] |”
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St. John's wort decreases plasma levels of mephenytoin in humans.
“| Mephenytoin | decrease plasma level of drug | [393] |”
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After St. John's wort is discontinued, as much as a week may be required for CYP3A activity to return to basal levels.
“Furthermore, once SJW has been discontinued, as much as a week may be required before CYP3A activity returns to basal levels [386].”
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St. John's wort decreases plasma levels of digoxin in humans.
“| Digoxin | decrease plasma level of drug | [49, 390-392] |”
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St. John's wort decreases plasma levels of atorvastatin in humans.
“| Atorvastatin | decrease plasma level of drug | [399] |”
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Individuals with the H1/H1 PXR haplotype pair appear more susceptible to St. John's wort-mediated CYP3A induction than those with H1/H2 or H2/H2 pairings.
“Recent studies indicate that individuals with the H1/H1 haplotype pair appear more susceptible to SJW-mediated CYP3A induction than subjects with H1/H2 or H2/H2 pairings [385].”
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- Rests on an assumption: PXR is polymorphic, and certain mutations produce significant functional defects in CYP3A transcription.
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St. John's wort decreases plasma levels of voriconazole in humans.
“| Voriconazole | decrease plasma level of drug | [394] |”
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St. John's wort extracts containing less than 1% hyperforin are less likely to produce clinically relevant herb-drug interactions, as shown by several clinical studies.
“Several clinical studies have demonstrated that SJW extracts containing less than 1 % hyperforin are less likely to produce clinically relevant herb-drug interactions [381][382][383][384].”
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St. John's wort decreases plasma levels of ivabradine in humans.
“| Ivabradine | decrease plasma level of drug | [389] |”
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St. John's wort decreases plasma levels of alprazolam in humans.
“| Alprazolam | decrease plasma level of drug | [401, 402] |”
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St. John's wort decreases plasma levels of indinavir in humans.
“| Indinavir | decrease plasma level of drug | [356] |”
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St. John's wort decreases plasma levels of warfarin in humans.
“| Warfarin | decrease plasma level of drug | [168, 216] |”
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Among PXR-regulated xenobiotic-metabolizing enzymes and transporters, CYP2C, CYP3A, and several ABC efflux transporters are most affected by St. John's wort.
“Of the XMEs and transporters regulated by PXR, those most affected by SJW are CYP subfamilies 2C and 3A as well as several ABC efflux transporters [370][371][372][373].”
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St. John's wort decreases plasma levels of verapamil in humans.
“| Verapamil | decrease plasma level of drug | [406] |”
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Concomitant administration of Ginkgo biloba enhances acetaminophen hepatotoxicity via CYP3A induction.
“Concomitant administration of G. biloba also enhanced the hepatotoxicity of acetaminophen via CYP3A induction [147].”
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Compared with conventional extract formulations, novel formulations can increase the oral bioavailability of various phytochemicals several fold.
“In each instance, when compared to conventional extract formulations, the oral bioavailability of various phytochemicals can be increased several fold.”
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- Findingreasoning
Prolonged administration of Ginkgo biloba extracts to rats reduces efficacy of nicardipine, tolbutamide, phenobarbital, propranolol, cyclosporine, and theophylline.
“The discovery that specific ginkgolides and flavonoids are ligands for several xenobiotic receptors provides an explanation for a host of recent in vivo studies in which prolonged administration of G. biloba extracts to rats, often in high doses, not only induced a multitude of XMEs [135-140] but reduced efficacy for several drug substrates: nicardipine [141], tolbutamide [142], phenobarbital [143”
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St. John's wort decreases plasma levels of nevirapine in humans.
“| Nevirapine | decrease plasma level of drug | [404] |”
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Bilobalide has no effect on nuclear receptors in these assays.
“Bilobalide exerted no effects on nuclear receptors in these assays.”
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Prolonged administration of Ginkgo biloba extracts to rats, often at high doses, induces multiple xenobiotic-metabolizing enzymes.
“The discovery that specific ginkgolides and flavonoids are ligands for several xenobiotic receptors provides an explanation for a host of recent in vivo studies in which prolonged administration of G. biloba extracts to rats, often in high doses, not only induced a multitude of XMEs [135-140] but reduced efficacy for several drug substrates: nicardipine [141], tolbutamide [142], phenobarbital [143”
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St. John's wort decreases plasma levels of talinolol in humans.
“| Talinolol | decrease plasma level of drug | [405] |”
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Prolonged administration of MDP-containing compounds induces CYP1A and CYP2B expression in several animal species.
“Prolonged administration of MDP-containing compounds has also been shown to induce CYP1A and CYP2B expression in several animal species [227-229].”
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Black pepper/piperine increases mean AUC of phenytoin by 16-133%.
“Drugs affected and the observed percent increase in mean AUC include phenytoin (16-133 %) [289, 291, 292], rifampicin (69%) [288], propranolol (103 %) [290], theophylline (96 %) [290], and nevirapine (170 %) [293]”
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Black pepper/piperine increases mean AUC of rifampicin by 69%.
“Drugs affected and the observed percent increase in mean AUC include phenytoin (16-133 %) [289, 291, 292], rifampicin (69%) [288], propranolol (103 %) [290], theophylline (96 %) [290], and nevirapine (170 %) [293]”
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Every prospective human trial of black pepper and/or piperine on drug pharmacokinetics has shown a profound improvement in oral bioavailability.
“To date, every prospective human trial investigating black pepperʼs and/or pi-perineʼs effect on drug pharmacokinetics has demonstrated a profound improvement in oral bioavailability.”
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Several in vivo studies contradicted cell-based reporter assay findings when bilobalide was implicated as an XME activator.
“However, several of these in vivo studies contradicted cell-based reporter assay findings when bilobalide was implicated as an XME activator [148-150].”
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In vitro assessments of allicin, fresh garlic, or commercial supplements either found no effect or modest inhibition (<50%) of human CYP2C9, CYP2C19, and CYP3A4.
“In vitro assessments of allicin, fresh garlic, or commercially prepared supplements (e.g., garlic oil and garlic powder) either found no effect [32,78] or modest inhibition (< 50%) of human CYP2C9, CYP2C19, and CYP3A4 isoforms [79,80].”
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Black cohosh supplementation (40-80 mg extract daily for 14 days) produced no demonstrable effects on digoxin and midazolam pharmacokinetics compared with clarithromycin or rifampin.
“black cohosh supplementation (40-80 mg extract daily delivering 3-6 mg triterpene glycosides for 14 days) produced no demonstrable effects on digoxin and MDZ pharmacokinetics [11,12].”
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Eight days of E. purpurea supplementation selectively modulated CYP3A activity in the intestine (inhibition) and liver (induction) of healthy volunteers.
“Gorski et al. concluded that 8 days of E. purpurea supplementation selectively modulated CYP3A activity in the intestine (inhibition) and liver (induction) of healthy volunteers [46].”
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Quantities of fukinolic and cimicifugic acids vary considerably among commercial black cohosh products.
“however, their quantities vary considerably among commercially available black cohosh products [9]”
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Many in vivo studies indicate that garlic oil and individual alkyl sulfides, most notably diallyl sulfide and allylmethylsulfide, inhibit murine and human CYP2E1.
“many in vivo studies indicate that garlic oil and individual alkyl sulfides, most notably diallyl sulfide and allylmethylsulfide, inhibit murine and human CYP2E1 [65][66][67][68].”
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Black cohosh extracts with DMSO moderately inhibited (~47%) SLCO2B1-mediated estrone-3-sulfate uptake in HEK cells expressing the transporter.
“Black cohosh extracts incorporating DMSO as a cosolvent moder-ately inhibited (~47%) uptake of estrone-3-sulfate, a SLCO2B1 substrate, into human embryonic kidney cells stably expressing the transporter [14].”
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- Interpretationreasoning
Echinacea supplements pose minimal risks for interacting with most conventional medications.
“Therefore, Echinacea supplements pose minimal risks for interacting with most conventional medications, an opinion concordant with that of other recent reviews [29,53].”
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- Rests on an assumption: The products and doses used in the cited clinical studies are representative of commercially available botanical supplements when taken as recommended.
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Healthy adults supplemented with E. purpurea for 14 or 30 days produced no clinically significant changes in CYP1A2, CYP2D6, CYP2E1, and CYP3A4 phenotypes.
“Gurley et al. found that healthy adults supplemented with E. purpurea for either 14 (800 mg extract daily) [49] or 30 days (1500 mg extract daily) [50] produced no clinically significant changes in CYP phenotypes.”
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Fukinolic and cimicifugic acids are potent inhibitors of CYP1A2, 2D6, 2C9, and 3A4 in vitro (IC50 < 13 μM).
“These compounds are potent (IC 50 < 13 µM) inhibitors of CYP1A2, 2D6, 2C9, and 3A4 in vitro [8]”
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Alkamides exhibit at least mild to moderate inhibition of CYP3A4 in most model systems tested, with magnitude dependent on alkamide content.
“A recent review of the bulk of these studies concluded that alkamides exhibit at least mild to moderate inhibiton of CYP3A4 in most of the model systems tested, with the magnitude dependent upon alkamide content [29].”
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Fourteen days of standardized E. purpurea (800 mg extract daily) had no effect on digoxin pharmacokinetics in healthy volunteers.
“Fourteen days of supplementation with a standardized, well-characterized E. purpurea product (800 mg extract daily) had no effect on digoxin (an ABCB1 substrate) pharmacokinetics in healthy volunteers [52].”
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Aged garlic extracts do not appear to inhibit major CYP isoforms in human liver microsomes.
“Aged garlic extracts (AGE), on the other hand, do not appear to inhibit any of the major CYP isoforms present in human liver microsomes [81].”
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- Interpretationreasoning
Standardized Echinacea extracts ingested per label recommendations are not likely to yield alkamide concentrations sufficient to dramatically modulate human CYP, ABC, and SLCO isoforms in vivo.
“Based on the collected evidence to date, it appears that dietary supplements formulated with standardized Echinacea extractswhen ingested per label recommendationsare not likely to yield alkamide concentrations sufficient enough to dramatically modulate human CYP, ABC, and SLCO isoforms in vivo.”
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Orally administered 23-epi-26-deoxyactein reaches systemic circulation intact at very low concentrations (<10 ng/mL).
“When administered orally, black cohoshʼs principal triterpene glycoside, 23-epi-26deoxyactein, reaches the systemic circulation intact, albeit in very low concentrations (< 10 ng/mL) [6].”
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A freeze-dried garlic supplement produced significant inhibition of CYP3A4 in vitro (>95%).
“A freeze-dried garlic supplement, however, produced significant inhibition of CYP3A4 in vitro (> 95%) [80].”
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- Premisenone given
Botanicals whose phytochemicals are mechanism-based CYP inhibitors or orphan nuclear receptor ligands are most likely to cause clinically important herb-drug interactions.
“Botanicals most likely to produce clinically important herb-drug interactions are those whose phytochemicals act as mechanism-based inhibitors of cytochrome P450 enzyme activity (e.g., Hydrastis canadensis, Piper nigrum, Schisandra chinensis) or function as ligands for orphan nuclear receptors (e.g., Hypericum perforatum).”
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Fexofenadine pharmacokinetics were not impacted by 28 days of E. purpurea supplementation.
“In addition, the pharmacokinetics of fexofenadine, a nonspecific ABCB1 and SLCO substrate, were not impacted by 28 days of E. purpurea supplementation [51].”
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- Premisecitation
Individual black cohosh triterpene glycosides are relatively weak inhibitors of human CYP3A4 in vitro (IC50 > 100 μM).
“In vitro studies found individual triterpene glycosides to be relatively weak inhibitors (IC 50 > 100 µM) of human CYP3A4 [7,8]”
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- Interpretationreasoning
Fukinolic and cimicifugic acids, not triterpene glycosides, may be responsible for inhibitory effects of whole black cohosh extracts.
“The inhibitory effects of whole black cohosh extracts may stem not from triterpene glycosides but rather fukinolic and cimicifugic acids.”
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Black cohosh triterpene glycosides are unlikely to inhibit human XMEs in vivo.
“This apparent lack of biotransformation bolsters the idea that black cohosh triterpene glycosides are unlikely to be inhibitors of human XMEs in vivo.”
Quote in the paperSubstantial claim - Interpretationreasoning
Standardized black cohosh supplements at recommended doses pose little risk for herb-drug interactions.
“Nevertheless, based on the currently available data, standardized black cohosh supplements, when taken at recommended doses, pose little risk for herb-drug interactions.”
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- Interpretationreasoning
Black cohosh does not appear to be a potent modulator of human drug metabolism.
“At present, black cohosh does not appear to be a potent modulator of human drug metabolism.”
Quote in the paperSubstantial claim - Interpretationcitation
Black cohosh is not a potent modulator of human CYP3A4 or ABCB1 activity in vivo.
“These findings suggest that black cohosh is not a potent modulator of human CYP3A4 or ABCB1 activity in vivo.”
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Black cohosh supplementation had no clinically significant effects on phenotypic measures of human CYP1A2, 2E1, or 2D6 activity.
“Black cohosh supplementation also had no clinically significant effects on phenotypic measures of human CYP1A2, 2E1, or 2D6 activity [13].”
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- Interpretationreasoning
Clinical and nonclinical evidence on ginseng extracts' effects on XMEs and transporters is particularly confusing due to an assortment of variables.
“From a drug interaction perspective, clinical and nonclinical evidence regarding ginseng extracts and their effects on XMEs and transporters is particularly confusing.This confusion stems from an assortment of variables affecting”
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The literature on ginseng's effects on drug-metabolizing enzymes and transporters is confusing because ginsenoside disposition varies with ginsenoside type and content, preabsorptive deglycosylation, membrane permeability, gut microflora, and ABC transporter efflux.
“This confusion stems from an assortment of variables affecting ginsenoside disposition.These include, but are not limited to, variability in ginsenoside type and content [190,191], degree of preabsorptive deglycosylation [192][193][194][195], poor membrane permeability [197], interindividual differences in gut microflora [192][193][194], and enteric efflux by ABC transporters [198,199].”
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- Premisecitation
Subsequent studies of prolonged garlic supplementation on other CYP3A4 substrates failed to note significant changes.
“Subsequent studies examining the prolonged effects of garlic supplementation on other CYP3A4 substrates, however, failed to note any significant changes [95][96][97].”
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- Interpretationreasoning
Daily doses of G. biloba exceeding 240 mg/day may increase prospects for interactions.
“However, daily doses exceeding 240 mg/day may increase prospects for interactions.”
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Prolonged consumption of garlic extract appears to modestly induce human ABCB1.
“On the other hand, prolonged consumption of garlic extract appears to modestly induce the human efflux transporter ABCB1.”
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Diallyl sulfide (~0.2 mg/kg) reduced plasma 6-hydroxychlorzoxazone/chlorzoxazone ratios by an average of 31% in healthy volunteers.
“Loizou and Crocker observed that administration of diallyl sulfide (~0.2 mg/kg) to healthy volunteers reduced plasma 6-hydroxychlorzoxazone/chlorzoxazone ratios (a phenotypic measure of CYP2E1 activity) by an average of 31% [92].”
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- Interpretationreasoning
Standardized G. biloba extracts at doses of 240 mg/day or less do not pose a risk for clinically relevant herb-drug interactions.
“In summary, dosage forms containing standardized G. biloba extracts, when administered at doses of 240 mg/day or less, do not pose a risk for clinically relevant herb-drug interactions.”
Quote in the paperSubstantial claim- Rests on an assumption: The products and doses used in the cited clinical studies are representative of commercially available botanical supplements when taken as recommended.
- Premisecitation
21 days of garlic powder supplementation reduced saquinavir mean AUC, 8-hour trough concentrations, and Cmax by 50%.
“21 days of twice daily supplementation with garlic powder (~9 mg allicin and 23 mg alliin) reduced by 50 % the mean AUC, 8-hour trough concentrations, and mean maximum plasma concentrations (C max ) of the protease inhibitor saquinavir [93].”
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- Premisecitation
No clinically important garlic-mediated interactions have been reported for warfarin.
“Nor have any clinically important garlic-mediated interactions been reported for warfarin, a recognized substrate for CYP2C9 and 3A4 [100,101].”
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- Interpretationcitation
Discrepancies in G. biloba's effect on rat and human XMEs in vivo appear dose related rather than due to species differences in PXR activation.
“Discrepancies in G. bilobaʼs effect on rat and human XMEs in vivo do not appear to reflect species differences in PXR activation [129, 179], but rather seem to be dose related [136, 139].”
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- cites [179]
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- cites [136]
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- cites [139]
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- Interpretationcitation
Evidence from human studies implies that only CYP2E1 substrates are significantly affected by garlic.
“yet the evidence implies that only substrates of CYP2E1 are significantly affected [90,92,98].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [90]
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- cites [92]
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- cites [98]
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- Interpretationreasoning
Most commercially available garlic supplements pose only a limited risk for clinically important herb-drug interactions.
“Taken together the accumulated findings imply that most commercially available garlic supplements pose only a limited risk for producing clinically important herb-drug interactions.”
Quote in the paperSubstantial claim- Rests on an assumption: The products and doses used in the cited clinical studies are representative of commercially available botanical supplements when taken as recommended.
- Premisenone given
Evidence from in vitro and animal investigations points to G. biloba extracts and constituents as inducers of XME and transporter activity.
“Evidence from in vitro and animal investigations clearly points to G. biloba extracts and their constituents as inducers of XME and transporter activity.”
Quote in the paperNot a substantial claim - Premisecitation
Highly polar, extensively glycosylated ginsenosides are relatively weak modulators of human drug-metabolizing enzymes and transporters.
“It is now clear that highly polar, extensively glycosylated ginsenosides (e.g., Rb1, Rb3, Rg3, Re, Rg1, Rg2) are relatively weak modulators of human XMEs and transporters [37,120,[200][201][202][203][204][205][206][207].”
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- cites [200][201][202][203][204][205][206][207]
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- Interpretationcitation
The few studies showing a modulatory effect of G. biloba on drug disposition do not appear clinically important when compared with FDA drug interaction criteria.
“when compared to FDA guidelines on drug interaction criteria [177, 178], those few studies demonstrating a modulatory effect of G. biloba on drug disposition do not appear to be clinically important.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [177]
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- cites [178]
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- Interpretationreasoning
The indinavir discrepancy may stem from indinavir's high oral bioavailability, making it a less effective probe for herb-mediated changes in CYP3A activity.
“This discrepancy may stem from the relatively high oral bioavailability of indinavir, which renders it a less effective probe for assessing herb-mediated changes in CYP3A activity.”
Quote in the paperSubstantial claim - Interpretationreasoning
The interaction risk for ginseng is low.
“Interaction risk: low.”
Quote in the paperSubstantial claim - Interpretationreasoning
The interaction risk for goldenseal is high.
“Interaction risk: high.”
Quote in the paperSubstantial claim - Interpretationreasoning
Whatever effect P. quinquefolius extracts might have on human CYP2C9 activity, its magnitude does not reach clinical significance.
“Therefore, it appears that whatever effect(s) P. quinquefolius extracts might have on human CYP2C9 activity, their magnitude does not reach clinical significance.”
Quote in the paperSubstantial claim - Premisecitation
Subsequent clinical trials with P. ginseng have not observed any influence on warfarin pharmacokinetics or pharmacodynamics.
“Subsequent clinical trials with P. ginseng, however, have failed to observe any influence on warfarin pharmacokinetics [216,222] or pharmacody-namics [216,218,222].”
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- Premisecitation
Even higher ginsenoside concentrations, above 100 μM, are required to induce CYP1A1, CYP2C9, and CYP3A4 activity in human liver cells and microsomes.
“This also holds true for the even higher ginsenoside concentrations (> 100 µM) required for inducing CYP1A1 [208], CYP2C9, and CYP3A4 [200] activity in human liver cells and microsomes.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [208]
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- cites [200]
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- Interpretationcitation
Goldenseal's propensity for herb-drug interactions appears limited to those mediated by CYPs.
“Therefore, goldensealʼs propensity for eliciting herbdrug interactions appears limited to those mediated by CYPs.”
Quote in the paperSubstantial claim - Premisecitation
Ginsenoside hydrolysis products, such as deglycosylated metabolites, competitively inhibit various CYPs and transporters, often at concentrations below 20 μM.
“However, the products of ginsenoside hydrolysis (e.g., deglycosylated metabolites) have been shown to competitively inhibit a variety of CYPs and transporters, oftentimes at concentrations well below 20 µM [203][204][205][206][207][208].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [203][204][205][206][207][208]
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- Premisecitation
A prospective study found that goldenseal supplementation had no significant effect on indinavir pharmacokinetics.
“Interestingly, another prospective study evaluating the influence of goldenseal supplementation on the pharmacokinetics of indinavir (a protease inhibitor and CYP3A4 substrate) failed to register any significant effects [233].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [233]
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- Premisecitation
MDP-containing phytochemicals in popular botanicals can act as mechanism-based inhibitors of CYPs in humans.
“In these species, MDP-containing PSMs (MDP-PSMs) often function as insecticides [225], but when consumed by humans they can act as mechanism-based inhibitors of CYPs [226,227].”
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- cites [226]
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- Premisecitation
Goldenseal's inhibition of human CYP2D6 in vivo was confirmed with other commercially available supplement brands.
“In addition, golden-sealʼs inhibition of human CYP2D6 in vivo was confirmed with other commercially available supplement brands [49].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [49]
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- Interpretationreasoning
Goldenseal may have its greatest impact on CYP3A substrates with high intestinal metabolism and low oral bioavailability.
“Thus, goldenseal may have its greatest impact on those CYP3A substrates exhibiting high intestinal metabolism and low oral bioavailability.”
Quote in the paperSubstantial claim - Premisereasoning
CYP-dependent oxidation of the methylenedioxy carbon to a carbene leads to a stable heme-adduct called a metabolic-intermediate complex.
“This type of inhibition is thought to arise from CYP-dependent oxidation of the methylenedioxy carbon to a carbene that subsequently interacts with CYP heme iron to produce a stable heme-adduct, termed a metabolic-intermediate (MI) complex”
Quote in the paperNot a substantial claim - Premisecitation
Goldenseal supplementation significantly inhibited CYP2D6 and CYP3A4 in healthy volunteers.
“Using phenotypic measures of CYP activity, Gurley et al. first observed that goldenseal supplementation significantly inhibited CYP2D6 and CYP3A4 in healthy volunteers [13].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13]
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- Premisecitation
Recent clinical evidence indicates that goldenseal's effect on digoxin disposition in humans is not significant.
“Recent clinical evidence, however, indicates that goldensealʼs effect on digoxin (an ABCB1 substrate with a narrow therapeutic index) disposition in humans is not significant [241].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [241]
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- Interpretationreasoning
The available evidence linking ginseng supplementation to potentially harmful drug interactions remains unconvincing.
“As a result, the available evidence that links ginseng supplementation to potentially harmful drug interactions remains unconvincing.”
Quote in the paperSubstantial claim - Premisecitation
Budzinski et al. first noted that commercial goldenseal extracts were potent in vitro inhibitors of CYP3A4.
“Using fluorometric microtiter plate assays, Budzinski et al. first noted that commercial extracts of Hydrastis canadensis were potent in vitro inhibitors of CYP3A4 [30].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30]
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- Premisecitation
Goldenseal reduced CYP3A-mediated conversion of testosterone to its 6β-hydroxy metabolite by 88%.
“Follow-up investigations by these authors found that goldenseal reduced CYP3A-mediated conversion of testosterone to its 6β-hydroxy metabolite by 88 % [31].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31]
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- Premisecitation
Piperine dramatically enhances the oral absorption of coadministered medications.
“One of the most compelling aspects of piperine is its ability to dramatically enhance the oral absorption of concomitantly administered medications [266,279,283,[288][289][290][291][292][293] .”
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- cites [288][289][290][291][292][293]
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- Premisecitation
Dihydromethysticin appears to induce CYP3A isoforms in vitro through activation of human PXR.
“Dihydromethysticin, like some other MDP-containing compounds, also appears to induce CYP3A isoforms in vitro through activation of human PXR [253].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [253]
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- Interpretationreasoning
Discrepancies between kava studies on CYP1A2 and 2E1 may be traced to variations in extract composition.
“Discrepancies between these studies with regard to kavaʼs effect on CYP1A2 and 2E1 may be traced to variations in extract compo- sition.”
Quote in the paperNot a substantial claim - Premisecitation
Piperine may promote drug absorption by modulating intestinal membrane permeability and stimulating increases in microvilli length.
“In addition to its inhibitory effects on XMEs and ABCB1, piperine may also promote drug absorption by modulating the permeability characteristics of intestinal membranes as well as through stimulating increases in microvilli length [287].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [287]
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- Interpretationreasoning
Lower amounts of methysticin and dihydromethysticin in kava extracts compared with goldenseal isoquinoline alkaloids may explain the difference in herb-drug interaction potentials.
“This, coupled with the fact that kava extracts often have lower amounts of methysticin and dihydromethysticin compared to the isoquinoline alkaloid content of goldenseal, may explain the difference in herb-drug interaction potentials for these two MDP-containing species.”
Quote in the paperSubstantial claim - Premisecitation
Piperine increased the pharmacodynamic effects of hexobarbital and zoxazolamine in a dose-dependent fashion.
“In addition, piperine increased the pharmacodynamic effects of hexobarbital and zoxazolamine in a dose-dependent fashion [266].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [266]
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- Premisecitation
Piperine's inhibitory effect on UGTs is more pronounced in intestinal epithelial cells than in hepatocytes.
“Piperineʼs inhibitory effect on UGTs is more pronounced in intestinal epithelial cells than hepatocytes [270].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [270]
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- Interpretationcitation
The apparent low potency of methysticin and dihydromethysticin as mechanism-based inhibitors in vivo may stem from the structure of their MDP side chains.
“The apparent low potency of methysticin and dihydromethysticin as mechanism-based inhibitors in vivo may stem from the structure of their MDP side chains.”
Quote in the paperNot a substantial claim - Premisecitation
Several animal studies report upregulation of GSTs, certain CYPs, and ABCs with long-term piperine exposure.
“While inhibition is clearly the most prevalent finding, especially upon acute exposure, several animal studies report upregulation of GSTs [284],certain CYPs [285,286], and ABCs [278,280,281] with long-term exposure to piperine, a finding in line with other studies examining chronic feeding of MDP-PSMs.”
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- cites [278]
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- cites [280]
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- Interpretationreasoning
Consumption of commercial kava supplements per label recommendations is not likely to affect the efficacy or toxicity of conventional medications.
“In short, consumption of commercially available kava supplements per product label recommendations is not likely to affect the efficacy or toxicity of conventional medications.”
Quote in the paperSubstantial claim - Premisereasoning
Schisandra MDP-PSMs are modulators of mammalian XMEs and transporters.
“Like many MDP-PSMs, those present in Schisandra species are modulators of mammalin XMEs and transporters.”
Quote in the paperSubstantial claim - Premisecitation
Follow-up studies found that piperine was a noncompetitive inhibitor of various murine hepatic monooxygenases and UGTs.
“Follow-up studies by Atalʼs group observed that piperine administration was a noncompetitive inhibitor of various murine hepatic monoxygenases as well as UGTs [267].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [267]
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- Premisecitation
Twenty mg of piperine produced an almost 20-fold increase in curcumin AUC.
“In another study, 20 mg of piperine produced an almost 20-fold increase in curcumin AUC [296].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [296]
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- Interpretationreasoning
The concern is particular when CYP3A and/or ABCB1 substrates are ingested with piperine or piperamides in excess of 10 mg.
“This may be of particular concern when CYP3A and/or ABCB1 substrates are ingested concomitantly with piperine or piperamides in excess of 10 mg.”
Quote in the paperSubstantial claim - Premisecitation
When administered with 5 mg piperine, a twofold increase in curcumin AUC was observed in healthy volunteers.
“When administered with 5 mg of piperine, a twofold increase in curcumin AUC was observed in healthy volunteers [294].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [294]
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- Premisecitation
Nakajima et al. noted that MDP-containing compounds with short, nonbulky side chains were less effective inhibitors of CYP activity.
“In examining a series of MDP-containing compounds, Nakajima et al. noted that those with short, nonbulky side chains were less effective inhibitors of CYP activity [230].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [230]
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- Premisecitation
Fourteen days of supplementation with well-characterized kava products had no clinically relevant effects on human CYP2D6, CYP3A4, or ABCB1 activity.
“Subsequent studies conducted by Gurleyʼs group found that, when compared to known CYP inducers and inhibitors, 14 days of supplementation with well-characterized kava products had no clinically relevant effects on human CYP2D6, CYP3A4, or ABCB1 activity [52,232,241].”
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- Premisecitation
In rats, single doses of Schisandra extracts up to 250 mg/kg with CYP3A and/or ABCB1 substrates more than doubled drug AUCs, suggesting inhibition.
“When single doses of Schisandra extracts (≤ 250 mg/kg) were administered to rats concomitantly with CYP3A and/or ABCB1 substrates (e.g., midazolam [311], nifedipine [309], paclitaxel [314], tacrolimus [312]), drug AUCs more than doubled, suggesting inhibition.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [311]
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- Interpretationreasoning
The clinical data currently available strongly suggest that Schisandra extracts pose a significant risk for elevating blood levels of drugs that are CYP3A and/or ABCB1 substrates.
“Accordingly, the clinical data currently available strongly suggests that Schisandra extracts pose a significant risk for elevating blood levels of drugs that are CYP3A and/or ABCB1 substrates.”
Quote in the paperSubstantial claim - Interpretationreasoning
Taken together, standard milk thistle products generate flavanolignan concentrations in vivo that are incapable of affecting most human XMEs and transporters.
“Taken together, these findings imply that standard milk thistle products generate flavanolignan concentrations in vivo that are incapable of affecting most human XMEs and transporters.”
Quote in the paperSubstantial claim - Interpretationreasoning
Unlike murine study results, prospective clinical trials assessing Schisandra's effect on CYP3A and/or ABCB1 substrate pharmacokinetics were not biphasic.
“Unlike the murine study results, prospective clinical trials assessing Schisandra's effect on CYP3A and/or ABCB1 substrate pharmacokinetics were not biphasic.”
Quote in the paperSubstantial claim - Premisereasoning
St. John's wort is well known for inducing the activity of several XMEs and transporters, thereby reducing the efficacy of many prescription medications.
“While recognized as a natural antidepressant, SJW is equally well known for its ability to induce the activity of several XMEs and transporters, thereby reducing the efficacy of a multitude of prescription medications.”
Quote in the paperSubstantial claim - Premisecitation
Hyperforin's mode of action appears unique: it does not interact directly with uptake transporters but elevates intracellular sodium concentration, thereby inhibiting gradient-driven neurotransmitter reuptake.
“Hyperforinʼs mode of action appears unique in that the phytochemical does not interact directly with uptake transporters but elevates intracellular sodium concentration, thereby inhibiting gradient-driven neurotransmitter reuptake [368].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [368]
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- Premisecitation
At concentrations exceeding 30 μM, silybin diastereomers have been reported to function as mechanism-based inhibitors of CYP2C9 and 3A4.
“At concentrations exceeding 30 µM, silybin diastereomers have been reported to function as mechanism-based inhibitors of CYP2C9 and 3A4 [336].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [336]
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- Premisecitation
UGT1A1 may be the XME most easily inhibited by milk thistle, with an IC50 value of 1.4 μM.
“UGT1A1, however, may be the XME most easily inhibited by milk thistle with an IC 50 value of 1.4 µM [336].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [336]
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- Premisecitation
In vitro studies indicate that Schisandra MDP-PSMs are competitive and noncompetitive inhibitors of murine and human CYP isoforms.
“A number of in vitro studies also point to Schisandra MDP-PSMs as both competitive and noncompetitive inhibitors of murine and human CYP isoforms [307][308][309][310][311][312].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [307][308][309][310][311][312]
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- Premisecitation
This finding supports Brantley et al.'s observation that CYP2C9 appeared most vulnerable to inhibition by clinically achievable concentrations of silybin B.
“This finding supports that of Brantley et al. who noted that CYP2C9 appeared most vulnerable to inhibition by clinically achievable concentrations of silybin B [340].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [340]
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- Premisecitation
Cmax values for unconjugated silybin A and B rarely exceeded 20 ng/mL for single 600 mg doses of milk thistle extract in healthy volunteers.
“As an example, C max values for unconjugated silybin A and B (the two most prevalent flavanolignans in milk thistle products) rarely exceeded 20 ng/ mL for single 600 mg doses of milk thistle extract in healthy volunteers [330].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [330]
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- Premisecitation
A recent clinical trial of Siliphos for chemotherapy-related hepatotoxicity in childhood acute lymphoblastic leukemia observed no adverse interactions between milk thistle and methotrexate, 6-mercaptopurine, or vincristine during 28-day supplementation.
“A recent clinical trial of Siliphos ® for treatment of chemotherapy-related hepatotoxicity in childhood acute lymphoblastic leukemia suggests otherwise, as investigators observed no adverse interactions between milk thistle and methotrexate, 6-mercaptopurine, or vincristine during the 28-day course of supplementation [365].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [365]
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- Premisecitation
SLC1B1 exhibited an IC50 value less than 4 μM for silymarin.
“SLC1B1 also exhibited an IC 50 value less than 4 µM for silymarin [347].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [347]
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- Premisecitation
Whether Schisandra was administered once or for up to 14 consecutive days, AUCs of talinolol, tacrolimus, and midazolam were increased 1.5-, 2.1-, and 2.0-fold, respectively.
“Whether Schisandra was administered once or for up to 14 consecutive days, AUCs of talinolol (ABCB1 substrate) [172], tacrolimus (CYP3A4/ABCB1 substrate) [317,318], and midazolam (CYP3A4 substrate) [319] were increased 1.5-, 2.1-, and 2.0-fold, respectively.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [172]
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- Premisecitation
Gomisin C's inhibitory effect was stronger than that of ketoconazole, a known potent CYP3A4 inhibitor.
“Moreover, the inhibitory effect of gomisin C was stronger than that of ketoconazole, a known potent CYP3A4 inhibitor [308].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [308]
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- Premisecitation
Gomisins B, C, and G are particularly effective inhibitors of human CYP3A4, with IC50 values below 1.5 μM.
“In particular, gomisins B, C, and G were shown to be particularly effective inhibitors of human CYP3A4 with IC 50 values < 1.5 µM [308].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [308]
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- Interpretationreasoning
Low bioavailability of milk thistle components stems from poor water solubility of silymarin phytochemicals combined with extensive presystemic metabolism and biliary secretion.
“This stems from a combination of the poor water solubility of silymarin phy- tochemicals coupled with extensive presytemic metabolism (both phase I and II) and biliary secretion.”
Quote in the paperNot a substantial claim - Premisecitation
At doses exceeding 1500 mg daily, there was evidence of nonlinear pharmacokinetics.
“At doses exceeding 1500 mg daily, there was also evidence of nonlinear pharmacokinetics [331].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [331]
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- Premisecitation
An unequivocal conclusion from clinical studies is that milk thistle has an excellent safety profile.
“However, an unequivocal conclusion gleaned from the clinical studies is that milk thistle has an excellent safety profile [322][323][324][325][326].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [322][323][324][325][326]
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- Premisecitation
Phosphatidylcholine complexes, or phytosomes, improve flavanolignan bioavailability three to five times compared with conventional milk thistle extract formulations.
“Marketed as Silipide ® and Siliphos ® , these phosphatidylcholine complexes, or phytosomes, exhibit improvements in flavanolignan bioavailability three to five times those of conventional milk thistle extract formulations [348][349][350][351][352].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [348][349][350][351][352]
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- Premisecitation
Hyperforin functions as a broad-based neurotransmitter reuptake inhibitor, affecting synaptosomal uptake of serotonin, dopamine, norepinephrine, glutamate, and GABA with similar efficiency.
“As an antidepressant, hyperforin functions as broad-based neurotransmitter reuptake inhibitor, affect-ing the synaptosomal uptake of serotonin, dopamine, norepinephrine, glutamate, and gamma-aminobutyric acid with similar efficiency.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Based on existing clinical data, the drug interaction risk for milk thistle products appears minimal.
“Therefore, based upon the existing clinical data, the drug interaction risk for milk thistle products appears minimal.”
Quote in the paperSubstantial claim - Premisecitation
Even with 700 mg milk thistle extract every 8 hours for 7 days, maximum steady-state concentrations of silybin A and B rarely exceeded 1.5 μg/mL.
“Even when milk thistle extract (700 mg) was administered every 8 hours for 7 days, the maximum steady state concentrations of silybin A and B rarely exceeded 1.5 µg/mL [331].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [331]
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- Premisecitation
When administration periods exceeded 6 days, rat XME and transporter function were consistently induced.
“However, when administration periods exceeded 6 days, rat XME and transporter function were consistently induced [310,311,315,316].”
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- Premisecitation
Hyperforin is a high-affinity ligand for human PXR.
“The prenylated phloroglucinol is a high-affinity ligand for human PXR, an orphan nuclear receptor selectively expressed in the liver and intestine that mediates the induction of XME and efflux transporter gene transcription [375][376][377].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [375]
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- Premisecitation
Liver disease increases milk thistle flavanolignan exposure.
“Liver disease, however, does increase milk thistle flavanolignan exposure.”
Quote in the paperNot a substantial claim - Premisecitation
Human PXR mediates the induction of xenobiotic-metabolizing enzyme and efflux transporter gene transcription.
“The prenylated phloroglucinol is a high-affinity ligand for human PXR, an orphan nuclear receptor selectively expressed in the liver and intestine that mediates the induction of XME and efflux transporter gene transcription [375][376][377].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [375]
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- Interpretationcitation
PXR haplotype is another factor affecting the magnitude of hyperforin's effect on CYP3A expression and drug efficacy.
“In addition to content variability, another factor affecting the magnitude of hyperforinʼs effect on CYP3A expression and drug efficacy is PXR haplotype.”
Quote in the paperNot a substantial claim- Rests on an assumption: PXR is polymorphic, and certain mutations produce significant functional defects in CYP3A transcription.
- Interpretationreasoning
St. John's wort-mediated interactions reduce drug efficacy.
“As a result, more than 70% of all prescription medications are susceptible to SJW-mediated interactions, the consequences of which are decreased oral bioavailability, enhanced systemic clearance, and reduced drug efficacy.”
Quote in the paperSubstantial claim - Premisecitation
Plasma concentrations of hyperforin often achieved in humans are approximately 100-300 nM.
“According to one estimate, hyperforin is the most potent PXR activator discovered to date [375], with a half-maximal effective concentration (EC 50 ) of 23 nMa value well below plasma concentrations often achieved in humans (~100-300 nM) [378,379].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [378]
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- cites [379]
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- Premisecitation
Hyperforin has an elimination half-life of 8-12 hours.
“(Unlike many of the unique phytochemicals described previously, hyperforin is bioavailable and exhibits an elimination half-life of 8-12 hours, thus allowing for significant accumulation with repeated dosing [378,379].)”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [378]
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- Interpretationreasoning
More than 70% of all prescription medications are susceptible to St. John's wort-mediated interactions.
“As a result, more than 70% of all prescription medications are susceptible to SJW-mediated interactions, the consequences of which are decreased oral bioavailability, enhanced systemic clearance, and reduced drug efficacy.”
Quote in the paperNot a substantial claim - Interpretationcitation
Repeated dosing of hyperforin allows significant accumulation.
“(Unlike many of the unique phytochemicals described previously, hyperforin is bioavailable and exhibits an elimination half-life of 8-12 hours, thus allowing for significant accumulation with repeated dosing [378,379].)”
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- Premisecitation
Hyperforin has a half-maximal effective concentration (EC50) of 23 nM.
“According to one estimate, hyperforin is the most potent PXR activator discovered to date [375], with a half-maximal effective concentration (EC 50 ) of 23 nMa value well below plasma concentrations often achieved in humans (~100-300 nM) [378,379].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [375]
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- Premisecitation
Hyperforin is bioavailable.
“(Unlike many of the unique phytochemicals described previously, hyperforin is bioavailable and exhibits an elimination half-life of 8-12 hours, thus allowing for significant accumulation with repeated dosing [378,379].)”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [378]
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- cites [379]
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- Interpretationreasoning
St. John's wort has a high interaction risk.
“Interaction risk: high.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Table 1
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- Interpretationreasoning
St. John's wort-mediated interactions decrease oral bioavailability.
“As a result, more than 70% of all prescription medications are susceptible to SJW-mediated interactions, the consequences of which are decreased oral bioavailability, enhanced systemic clearance, and reduced drug efficacy.”
Quote in the paperSubstantial claim - Premisecitation
Hyperforin is the most potent PXR activator discovered to date, according to one estimate.
“According to one estimate, hyperforin is the most potent PXR activator discovered to date [375], with a half-maximal effective concentration (EC 50 ) of 23 nMa value well below plasma concentrations often achieved in humans (~100-300 nM) [378,379].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [375]
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- Interpretationreasoning
St. John's wort-mediated interactions enhance systemic clearance.
“As a result, more than 70% of all prescription medications are susceptible to SJW-mediated interactions, the consequences of which are decreased oral bioavailability, enhanced systemic clearance, and reduced drug efficacy.”
Quote in the paperSubstantial claim - Premisecitation
Phytochemical content can vary considerably, as is the case with hyperforin.
“As with all botanicals, phytochemical content can vary considerably and such is the case with hyperforin [380,381].”
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- Interpretationreasoning
Most botanical dietary supplements pose only minimal risk of modulating human drug metabolism.
“As a result, most botanical dietary supplements pose only minimal risks for modulating human drug metabolism.”
Quote in the paperSubstantial claim - Premisecitation
Ginkgo extracts and individual terpene lactones can induce expression of several CYP, UGT, and ABC isoforms in rat and human primary hepatocytes and human mammary epithelial cells.
“In contrast, ginkgo extracts and individual terpene lactones appear capable of inducing the expression of several CYP, UGT, and ABC isoforms in rat [128-130] and human primary hepatocytes[113, 114, 130, 131] as well as human mammary epithelial cells [132].”
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- Interpretationreasoning
In vitro studies and compelling case reports suggest that many more botanical supplements may be potent modulators of human drug disposition.
“Nevertheless, in vitro studies and compelling case reports suggest that many more botanical supplements may indeed be potent modulators of human drug disposition.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Many botanicals whose drug interaction potential is minimized as conventional dry extracts may increase significantly when ingested as novel delivery formulations.
“Accordingly, many botanicals whose drug interaction potential is minimized when administered as conventional dry extracts may increase significantly upon ingestion of formulations utilizing novel delivery systems.”
Quote in the paperSubstantial claim- Rests on an assumption: No clinical assessments of the herb-drug interaction potential of botanical extracts incorporating novel formulations have been reported to date.
- Interpretationreasoning
Phytochemicals previously eliminated by the xenobiotic defense system may emerge as inducers and/or inhibitors of human xenobiotic-metabolizing enzymes and transporters.
“Phytochemicals that heretofore had been casualties of manʼs xenobiotic defense system may emerge as inducers and/or inhibitors of human XMEs and transporters.”
Quote in the paperSubstantial claim - Interpretationreasoning
Several distinct phytochemicals can inactivate or hijack the controls of the gastrointestinal defense network.
“However, several distinct PSMs can either inactivate or highjack the controls of this innate gastrointestinal defense network.”
Quote in the paperNot a substantial claim - Interpretationreasoning
MDP-containing phytochemicals, as mechanism-based CYP inhibitors, may increase the toxicity of allopathic medications.
“MDP-PSMs, functioning as mechanism-based inhibitors of CYPs, may potentiate the toxicity of allopathic medications, whereas potent nuclear receptor ligands like hyperforin may dramatically reduce drug efficacy.”
Quote in the paperNot a substantial claim - Premisecitation
Several dietary supplement manufacturers have recently incorporated novel formulation methods for botanical extracts to improve oral absorption.
“Recognizing that poor dissolution characteristics represent major obstacles to phytochemical bioavailability and efficacy, several dietary supplement manufacturers have recently incorporated novel methods of formulating botanical extracts as a means of improving oral absorption [387,388].”
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- Premisecitation
Poor dissolution characteristics are major obstacles to phytochemical bioavailability and efficacy.
“Recognizing that poor dissolution characteristics represent major obstacles to phytochemical bioavailability and efficacy, several dietary supplement manufacturers have recently incorporated novel methods of formulating botanical extracts as a means of improving oral absorption [387,388].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [387]
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- Rests on an assumption: Poor dissolution characteristics are major obstacles to phytochemical bioavailability and efficacy.
- Interpretationreasoning
Potent nuclear receptor ligands such as hyperforin may dramatically reduce drug efficacy.
“MDP-PSMs, functioning as mechanism-based inhibitors of CYPs, may potentiate the toxicity of allopathic medications, whereas potent nuclear receptor ligands like hyperforin may dramatically reduce drug efficacy.”
Quote in the paperNot a substantial claim - Interpretationcitation
Whether CYP inhibition or induction predominates in vivo may depend on the length and bulk of MDP side chains and the individual CYP isoform examined.
“Whether CYP inhibition or induction predominates in vivo may depend upon the length and bulk of MDP side chains as well as the individual CYP isoform examined[230].”
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- Premisecitation
CYP isoforms are inactivated by MDP-PSMs through formation of MI complexes.
“It is through the formation of MI complexes that CYP isoforms are inactivated by MDP-PSMs [227, 228].”
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- May combine two claims. 67
- The quote only partly states this claim. 16
- Classified as probably not a substantial claim. 15
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FindingcitationOf 29 prospective clinical trials, 23 observed no significant effects of G. biloba on drug disposition, 5 observed modest inhibition, and 3 showed evidence of CYP3A4, CYP2C9, or CYP2C19 induction.
“Of the 29 studies (many of which evaluated more than one drug), 23 observed no significant effects of G. biloba on drug disposition, 5 observed a modest inhibitory effect [153, 154, 166, 172, 173], and 3 demonstrated evidence of CYP3A4 [168], CYP2C9 [164], and CYP2C19 [151] induction.”
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FindingcitationSt. John's wort alters the pharmacokinetics of multiple medications, as confirmed by many clinical studies.
“Since that time, a plethora of clinical studies have borne out SJWʼs effect on the pharmacokinetics of various medications [370][371][372][373][374].”
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FindingcitationSt. John's wort decreases plasma levels of ethinylestradiol in humans.
“| Ethinylestradiol | decrease plasma level of drug | [410-412] |”
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FindingcitationSt. John's wort decreases plasma levels of cyclosporine in humans.
“| Cyclosporine | decrease plasma level of drug | [395, 414-416] |”
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FindingcitationSt. John's wort decreases plasma levels of omeprazole in humans.
“| Omeprazole | decrease plasma level of drug | [421] |”
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FindingcitationSt. John's wort decreases plasma levels of irinotecan in humans.
“| Irinotecan | decrease plasma level of drug | [407] |”
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FindingcitationSt. John's wort decreases plasma levels of norethindrone in humans.
“| Norethindrone | decrease plasma level of drug | [410, 411] |”
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FindingcitationSt. John's wort decreases plasma levels of tacrolimus in humans.
“| Tacrolimus | decrease plasma level of drug | [417-419] |”
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FindingcitationIn cell-based reporter assays, ginkgolides A and B activate PXR, while quercetin and kaempferol activate PXR, CAR, and AhR.
“Cell-based reporter assays in HepG2 [121, 131] and LS180 [133] and other cell lines [132, 134] revealed that ginkolides A and B are activators of PXR, whereas quercetin and kaempferol activated PXR, CAR, and AhR.”
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FindingcitationSt. John's wort decreases plasma levels of finasteride in humans.
“| Finasteride | decrease plasma level of drug | [422] |”
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FindingcitationSt. John's wort decreases plasma levels of nifedipine in humans.
“| Nifedipine | decrease plasma level of drug | [153, 385] |”
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FindingcitationSt. John's wort decreases plasma levels of methadone in humans.
“| Methadone | decrease plasma level of drug | [420] |”
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FindingcitationSt. John's wort decreases plasma levels of imatinib in humans.
“| Imatinib | decrease plasma level of drug | [408, 409] |”
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FindingcitationSt. John's wort decreases plasma levels of gliclazide in humans.
“| Gliclazide | decrease plasma level of drug | [413] |”
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FindingcitationSt. John's wort decreases plasma levels of chlorzoxazone in humans.
“| Chlorzoxazone | decrease plasma level of drug | [90, 98] |”
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FindingreasoningMany phytochemicals modulate human xenobiotic-metabolizing enzymes and transporters in vitro, but this activity is rarely realized in vivo.
“As discussed in previous sections, many PSMs modulate human XMEs and transporters in vitro, but due to various factors, this activity is rarely realized in vivo.”
Quote in the paperNot a substantial claimThe quote only partly states this claim.
FindingcitationSt. John's wort decreases plasma levels of ketodesogestrel in humans.
“| Ketodesogestrel | decrease plasma level of drug | [412] |”
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FindingcitationBlack pepper/piperine increases mean AUC of propranolol by 103%.
“Drugs affected and the observed percent increase in mean AUC include phenytoin (16-133 %) [289, 291, 292], rifampicin (69%) [288], propranolol (103 %) [290], theophylline (96 %) [290], and nevirapine (170 %) [293]”
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FindingcitationMDPs with long bulky side chains appear to be more potent inhibitors of CYP1A2, CYP2C9, CYP2D6, and CYP3A4, whereas CYP2B6 and CYP2C19 are not inactivated.
“MDPs with long bulky side chains appear to be more potent inhibitors of CYP1A2, CYP2C9, CYP2D6, and CYP3A4, whereas CYP2B6 and CYP2C19 are not inactivated[230].”
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FindingcitationBlack pepper/piperine increases mean AUC of nevirapine by 170%.
“Drugs affected and the observed percent increase in mean AUC include phenytoin (16-133 %) [289, 291, 292], rifampicin (69%) [288], propranolol (103 %) [290], theophylline (96 %) [290], and nevirapine (170 %) [293]”
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FindingcitationBlack pepper/piperine increases mean AUC of theophylline by 96%.
“Drugs affected and the observed percent increase in mean AUC include phenytoin (16-133 %) [289, 291, 292], rifampicin (69%) [288], propranolol (103 %) [290], theophylline (96 %) [290], and nevirapine (170 %) [293]”
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PremisecitationSeveral Echinacea alkamides, but not caffeic acid conjugates, cross intestinal mucosa intact and reach systemic circulation.
“Permeability [22,23] and pharmacokinetic [24][25][26] studies indicate that several alkamides, but not caffeic acid conjugates, cross the intestinal mucosa reaching the systemic circulation intact.”
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Premisecitation28 days of E. purpurea supplementation produced modest reductions in midazolam AUC (27% decrease) but no significant effects on lopinavir, ritonavir, or fexofenadine pharmacokinetics.
“Penzak et al. reported that 28 days of E. purpurea supplementation in healthy volunteers (500 mg three times daily) produced modest reductions in midazolam AUC (27% decrease), but had no significant effects on the pharmacokinetics of lopinavir and ritonavir (CYP3A4 substrates), or fexofenadine (a purported ABCB1 and SLCO substrate) [51].”
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InterpretationreasoningFew interactions involving garlic products and CYP2E1 substrates have been reported, probably because few drugs are metabolized by CYP2E1.
“Despite inhibition of human CYP2E1 in vitro, few interactions involving garlic products and CYP2E1 substrates have been reported, a consequence that probably reflects the paucity of drugs metabolized by this enzyme.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationIndividual Echinacea alkamides are metabolized to varying degrees by several human CYPs, but metabolism is markedly reduced when they are combined in an extract.
“Individual Echinacea alkamides are metabolized to varying degrees by several human CYPs, but when combined (as in an extract), metabolism is markedly reduced [27][28][29].”
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PremisecitationAfter single doses of Echinacea alkamides (~11 mg), plasma concentrations vary considerably and maximum plasma levels do not exceed 350 ng/mL.
“Following single doses of Echinacea alkamides (~11 mg) administered as tablets manufactured from ethanolic liquid extracts, plasma concentrations varied considerably with maximum plasma levels not exceeding 350 ng/mL [26].”
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PremisecitationBlack cohosh products exhibit considerable variability in phytochemical profiles, and label claims for standardized marker compounds can deviate from actual content.
“black cohosh products exhibit considerable variability in phytochemical profiles, and label claims for “standardized” marker compounds can deviate considerably from actual content [9].”
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InterpretationcitationDiallyl sulfide is biotransformed by CYP2E1 to diallyl sulfoxide and diallyl sulfone, and diallyl sulfone is a mechanism-based inhibitor of the enzyme.
“This is likely a result of the CYP2E1-catalyzed biotransformation of diallyl sulfide to diallyl sulfoxide and diallyl sulfone, in which the latter is a mechanism-based inhibitor of the enzyme [66,69].”
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PremisecitationWhole black cohosh extracts inhibit CYP3A4 more than individual triterpene glycosides, suggesting synergy.
“while whole extracts elicited greater inhibition, a finding suggestive of synergy [7].”
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PremisecitationCommercial Echinacea supplements often contain extracts from various species and plant parts, so phytochemical profile and content vary considerably among products.
“Because commercially available Echinacea supplements often consist of extracts from various species and plant parts, considerable variation in phytochemical profile and content is common among products [16,21].”
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Premisenone givenExternal factors unrelated to phytochemical pharmacology can increase the drug interaction potential of botanical supplements.
“In addition, several external factors unrelated to phytochemical pharmacology can augment the drug interaction potential of botanical supplements.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationEGb 761 is a standardized concentrated extract containing 24% flavonoid glycosides, 6% terpene lactones, 5-10% organic acids, and other constituents.
“EGb 761 is a standardized, concentrated extract containing 24% flavonoid glycosides (e.g., quercetin, kaempferol, isorhamnetin), 6 % terpene lactones (3.1 % ginkgolides A, B, C, and J and 2.9 % bilobalide), 5-10 % organic acids, and other constituents [104].”
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PremisecitationProlonged garlic oil supplementation inhibited human CYP2E1 activity by almost 40% in young adults and 25% in elderly adults, with no modulatory effects on CYP1A2, CYP2D6, or CYP3A4.
“prolonged garlic oil supplementation (500 mg, three times daily for 28 days) inhibited human CYP2E1 activity in both young [90] and elderly adults [98] by almost 40% and 25 %, respectively; however, no modulatory effects were noted for CYP1A2, CYP2D6, or CYP3A4.”
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PremisecitationA 31% increase in duodenal ABCB1 expression correlated with a modest reduction in saquinavir AUC, while simvastatin and pravastatin pharmacokinetics were not significantly affected.
“A 31 % increase in the duodenal expression of human ABCB1 correlated with a modest reduction in saquinavir AUC while no significant effects were noted in the pharmacokinetic parameters of simvastatin (a CYP3A4 substrate) or pravastatin (an SLCO1B1 substrate).”
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PremisecitationP. ginseng and P. quinquefolius differ significantly in type and proportion of ginsenosides, with P. ginseng having a high Rg1:Rb1 ratio and P. quinquefolius a low ratio.
“P. ginseng and P. quinquefolius differ significantly in type and proportion of ginsenosides, with P. ginseng having a high Rg1 : Rb1 ratio and P. quinquefolius a low Rg1 : Rb1 ratio [191].”
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PremisecitationIngested ginsenosides undergo partial hydrolytic deglycosylation in the stomach and further deglycosylation in the large intestine by gut microflora glucosidases.
“When ingested, ginsenosides undergo partial hydrolytic deglycosylation in the stomach and are further deglycosylated in the large intestine through enzymatic glucosidase activity of gut microflora [190,[192][193][194].”
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PremisecitationAt high concentrations (~12 μg/mL), water-soluble AGE compounds induced ABCB1, ABCC2, and SLCO transporter activity in Caco-2 monolayers and rat intestine.
“When exposed to both Caco-2 cell monolayers and the rat intestine at high concentrations (~12 µg/mL), water-soluble compounds in AGE (e. g., S-allyl-L-cysteine) induced the activity of ABCB1, ABCC2, and SLCO transporters [86,87].”
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PremisecitationLarge doses of allicin (~150 mg daily) reduced omeprazole metabolism by inhibiting CYP2C19 in individuals with CYP2C19*1 alleles but not in CYP2C19*2 homozygotes.
“large doses of the organosulfur compound allicin (~150 mg daily) did reduce the metabolism of omeprazole by inhibiting CYP2C19 activity in individuals both homozygous and heterozygous for the CYP2C19*1 allele, but not for those homozygous for CYP2C19*2 [102].”
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InterpretationcitationIn Caco-2 and MDR1-MDCK monolayers, ginkgolides and bilobalide exhibited low absorptive permeability and high efflux, which would preclude their exposure to enteric XMEs.
“In Caco-2 and MDR1-MDCK cell monolayers, ginkgolides and bilobalide exhibited low absorptive permeability and high efflux [185]; two conditions that would further preclude their exposure to enteric XMEs.”
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Interpretationnone givenAmbiguity in ginseng clinical findings may be linked to differences in ginsenoside content of products evaluated.
“Ambiguity in clinical findings may be linked to differences in the ginsosenoside content of products evaluated.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationFollowing 240 mg doses of standardized G. biloba extracts, Cmax values for ginkgolides and bilobalide rarely exceeded 40 ng/mL, well below the 4000 ng/mL at which ginkgolides A and B activated PXR in vitro.
“Following 240 mg doses of standardized G. biloba extracts, C max values for ginkgolides and bilobalide rarely exceeded 40 ng/mL [180-182], concentrations well below the 4000 ng/mL at which ginkgolides A and B activated PXR in vitro [133].”
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PremisecitationGarlic's oil-soluble organosulfur compounds are not potent inhibitors of ABCB1 but may induce ABCC2 expression.
“The preponderance of in vitro data regarding ABC isoforms implies that garlicʼs oil-soluble organosulfur compounds are not potent inhibitors of the efflux transporter ABCB1 [80,[82][83][84][85] but may, however, induce ABCC2 expression [85].”
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InterpretationreasoningOnly human CYP2E1 appears to be inhibited by garlic oil products, and this interaction is not of great concern because few drugs are CYP2E1 substrates and most have broad therapeutic indices.
“Presently, only human CYP2E1 appears to be inhibited by garlic oil products, but because only a few drugs are substrates of CYP2E1 and most of those have fairly broad therapeutic indicies, this interaction is not cause for great concern.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationFourteen days of goldenseal supplementation, about 209 mg isoquinoline alkaloids daily, significantly increased midazolam AUC, Cmax, and elimination half-life, with effects proportional to clarithromycin 1000 mg daily.
“In subsequent investigations with the CYP3A4 probe midazolam, Gurley et al. further demonstrated that 14 days of goldenseal supplementation (~209 mg isoquinoline alklaoids daily) significantly increased midazolam AUC, C max , and elimination half-life, and that the effects were proportional to those produced by the well-recognized, mechanism-based inhibitor clarithromycin (1000 mg daily) [232].”
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PremisecitationYuan et al. found that P. quinquefolius reduced INR, peak plasma warfarin levels, and warfarin AUCs in healthy volunteers, with statistical significance.
“As single case reports cannot establish causation, a prospective clinical trial by Yuan et al. demonstrated that international normalized ratios (INR, a measure of anticoagulation), peak plasma warfarin levels, and warfarin AUCs were reduced by P. quinquefolius in healthy volunteers, and these effects reached statistical significance [221].”
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PremisecitationIn humans, berberine and hydrastine are readily absorbed and extensively metabolized, with berberine phase I metabolites preferentially sulfated and hydrastine metabolites primarily glucuronidated.
“In humans, both berberine and hydrastine are readily absorbed and extensively metabolized, with berberine phase I metabolites being preferentially sulfated, while those of hydrastine are primarily glucuronidated [243].”
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PremisecitationMethodological concerns about the Yuan et al. study include underpowering, inadequate sampling for AUC determination, and a non-stereoselective assay for warfarin enantiomers.
“however, several methodological concerns have been raised about the Yuan et al. study including it being underpowered, that inadequate sampling was used to determine AUC, and a non-stereoselective assay was used to measure warfarin enantiomers [222].”
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InterpretationcitationIn animal studies, P. ginseng or P. quinquefolius either mildly induce or have no significant effects on rat XMEs and ABCB1 activity in vivo.
“From these, it appears that P. ginseng or P. quinquefolius either mildly induce [209][210][211] or have no significant effects [212-214] on rat XMEs and ABCB1 activity in vivo.”
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PremisecitationHydrastine is a more potent CYP3A4 inhibitor, with an IC50 of 25 μM, than berberine, with an IC50 of 400 μM.
“They demonstrated that hydrastine was a more potent inhibitor of CYP3A4 (IC 50 = 25 µM) than berberine (IC 50 = 400 µM).”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationBerberine and hydrastine are MDP-PSMs that inhibit various CYP isoforms in vitro.
“Both berberine and hydrastine are MDP-PSMs that inhibit various CYP isoforms in vitro [10,30,31,34,36,37,231].”
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PremisecitationIn vitro concentrations of ginsenosides needed to inhibit most CYPs and transporters are above 50 μM and are unlikely to be reached in vivo under normal ginseng dosing.
“Ginsenoside concentrations necessary to inhibit most CYPs and transporters in vitro are not only high (> 50 µM), but are not likely to be realized in vivo, especially if normal dosing recommendations of ginseng products are followed [37,120,127,[200][201][202][203][204][205][206][207].”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [37]
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PremisecitationDissolution profiles show that berberine and hydrastine are rapidly and completely released from goldenseal extract formulations, producing intestinal luminal concentrations comparable to those required for CYP inhibition in vitro.
“Dissolution profiles of commercially available goldenseal supplements reveal that berberine and hydrastine are rapidly and completely released from extract formulations [242], producing intestinal luminal concentrations comparable to those required for CYP inhibition in vitro [241].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [242]
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- cites [241]
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InterpretationreasoningExtensive metabolism is conducive to MI complex formation and may explain goldenseal's penchant for CYP inhibition.
“Extensive metabolism is conducive to the formation of MI complexes and may explain goldensealʼs penchant for CYP inhibition.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationcitationProspective human trials of P. ginseng and P. quinquefolius on drug disposition show either no effect or mild induction, with warfarin being the most studied CYP2C9 substrate.
“Substantially more prospective human trials have investigated the effects of P. ginseng and P. quinquefolius supplementation on human drug disposition, with the CYP2C9 substrate, warfarin, being examined the most.Like the murine studies, clinical results fall into two catgories: no effect [90,98,[215][216][217][218][219] or mild induction [217,[220][221][222].”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [90]
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PremisecitationConvincing in vitro and animal evidence indicates that berberine is a substrate for certain ABC isoforms and may compete with other ABC substrates for efflux.
“There is convincing in vitro and animal evidence that berberine is a substrate for certain ABC isoforms [236][237][238][239][240], and thus, it may compete with other ABC substrates for efflux across intestinal and canalicular membranes.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [236][237][238][239][240]
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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningBecause cyclosporine is both a CYP3A4 and ABCB1 substrate, hydrastine and berberine could affect both proteins.
“Since cyclosporine is both a CYP3A4 and ABCB1 substrate, the activity of both of these proteins could conceivably be affected by hydrastine and berberine.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningBecause goldenseal isoquinoline alkaloids significantly inhibit CYP3A4 and CYP2D6, goldenseal's herb-drug interaction potential is considerable.
“Given that goldenseal isoquinoline alkaloids significantly inhibit both CYP3A4 and CYP2D6 activity (the two most important drug metabolizing enzymes in humans), its herb-drug interaction potential is deemed considerable.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationGurley et al. observed that 30 days of kava supplementation had no effect on CYP1A2, CYP2D6, or CYP3A4 activity, but significantly reduced CYP2E1 activity.
“In contrast, Gurley et al. observed that 30 days of kava supplementation in healthy volunteers had no effect on the phenotypic markers of CYP1A2, CYP2D6, or CYP3A4 activity; however, CYP2E1 activity was significantly reduced [13].”
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PremisecitationStructure-activity relationship studies with more than 35 analogues revealed that piperine is especially suited for CYP inhibition, and modifications to the MDP moiety or piperidine side chain significantly reduced potency.
“Moreover, structureactivity relationship studies involving more than 35 separate analogues revealed that piperine is especially suited for CYP inhibition [273].Modifications to either the MDP moiety or piperidine side chain significantly reduced its potency [273].”
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PremisecitationSubsequent studies confirmed piperine's effect on murine XMEs and found that piperine and other piperamides were selective inhibitors of human CYP3A4, CYP2D6, and ABCB1 in vitro.
“Subsequent studies confirmed piperineʼs effect on murine XMEs [268][269][270][271][272][273] and also found that it and other piperamides were selective inhibitors of human CYP3A4, CYP2D6, and ABCB1 in vitro [274,275,277,282].”
Quote in the paperNot a substantial claim0 of 5 sources checked- cites [268][269][270][271][272][273]
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PremisecitationAmple evidence indicates that Schisandra MDP-PSMs are both substrates and inhibitors of ABC efflux transporters in vitro.
“Ample evidence points to Schisandra MDP-PSMs as both substrates and inhibitors of ABC efflux transporters in vitro [300][301][302][303][304][305][306].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [300][301][302][303][304][305][306]
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PremisecitationMethysticin and dihydromethysticin are MDP-PSMs and potent mechanism-based inhibitors of CYPs in vitro at concentrations of 10 μM or less.
“Of these, methysticin and dihydromethysticin are both MDP-PSMs and potent (≤ 10 µM) mechanism-based inhibitiors of CYPs in vitro [247,249].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [247]
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PremisecitationRussman et al. found that chronic users of traditional kava beverages had significantly reduced CYP1A2 activity but no effect on CYP2C19, 2D6, 2E1, or 3A4 phenotypic markers.
“Russman et al. found that in chronic users of traditional kava-containing beverages (e. g., 7-27 g kavalactones per week) significantly reduced CYP1A2 activity, yet this practice had no effect on the phenotypic markers of CYP2C19, 2D6, 2E1, or 3A4 function [259].”
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InterpretationreasoningIn practically every case, piperine's effect can be considered clinically relevant, especially for drugs with narrow therapeutic indices.
“In practically every case, piperineʼs effect can be considered clinically relevant.This is especially so for drugs with narrow therapeutic indices.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationMethysticin and dihydromethysticin have good dissolution profiles in simulated intestinal fluid at pH above 4, favoring gut lumen concentrations above 10 μM.
“In addition, both methysticin and dihydromethysticin have good dissolution profiles in simulated intestinal fluid at pH values greater than 4, a property favorable for producing gut lumen concentrations in excess of 10 µM [242].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [242]
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PremisecitationPiperine and related piperamides function as insecticides in pepper plants but inhibit various XMEs and transporters in mammalian systems.
“These compounds function as insecticides in the pepper plant [263][264][265], but in mammalian systems they are inhibitors of various XMEs [266-277] and transporters [278][279][280][281][282][283].”
Quote in the paperNot a substantial claim0 of 10 sources checked- cites [263][264][265]
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PremisecitationTraditional kava beverages are aqueous extractions, while many commercial kava supplements are nonaqueous solvent extractions, and kavalactone profiles can vary considerably between the two processes.
“Traditional kava beverages are made from aqueous extractions of P. methysticum root, whereas formulations of many commercially available kava supplements are products of nonaqueous solvent extractions.Kavalactone profiles can vary considerably among the two extraction processes [245].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [245]
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPiperine has a broad safety profile.
“As an added benefit to enhancing phytochemical bioavailability, piperine also has a broad safety profile [260].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [260]
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PremisecitationMost in vitro data indicate that kava inhibits various CYPs and ABCB1, while other evidence suggests kava may activate PXR to induce CYP and ABCB1 activity.
“The preponderance of in vitro data points to kava as an inhibitor of various CYPs and ABCB1 [79,[245][246][247][248][249][250][251], whereas other evidence suggests kava may activate PXR to induce CYP and ABCB1 activity [252][253][254].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [79,[245][246][247][248][249][250][251]
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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone givenThe interaction risk for black pepper/piperine is high.
“Interaction risk: high.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSimilar bioavailability-enhancing effects on green tea polyphenols have been reported.
“Similar bioavailability enhancing effects on green tea polyphenols have also been reported [297].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [297]
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Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).
Interpretationnone givenThe interaction risk for kava is low.
“Interaction risk: low.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningExcessive use of black pepper or intake of dietary supplements formulated with P. nigrum or P. longum extracts may produce clinically significant interactions with drugs.
“However, excessive use of black pepper or intake of dietary supplements formulated with P. nigrum or P. longum extracts may produce clinically significant interactions with drugs.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
InterpretationreasoningWhen used in quantities typical for flavoring food, black pepper is not likely to affect the disposition of most medications.
“When used in quantities typical for flavoring food, black pepper is not likely to affect the disposition of most medications.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationRecent investigations reveal that hyperforin and other St. John's wort-related phytochemicals act synergistically through pharmacodynamic and pharmacokinetic mechanisms to alleviate depression.
“As previously mentioned in Part 1 of this review, recent investigations reveal that hyperforin and other SJW-related phytochemicals (e.g., adhyperfroin, hypericins, flavanol glycosides) act synergistically through both pharmacodynamic and pharmacokinetic mechanisms to alleviate depression [369].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [369]
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Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).
Interpretationnone givenThe interaction risk for milk thistle is low.
“Interaction risk: low.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationIn subjects with the CYP2C9*1/*1 genotype, a 14-day course of silymarin produced a 2-fold increase in losartan AUC and Cmax, but these parameters were not affected in subjects with the CYP2C9*1/*3 genotype.
“In subjects with the CYP2C9*1/*1 genotype, a 14day course of silymarin produced a 2-fold increase in losartan AUC and C max , but these parameters were not affected in subjects with the CYP2C9*1/*3 genotype.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningBased on these data, Schisandra appears to be a potent inhibitor, not an inducer, of human XMEs and transporters.
“Based on these data, it appears that Schisandra is a potent inhibitor, not an inducer, of human XMEs and transporters.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationMany clinical trials have demonstrated that St. John's wort has efficacy superior to placebo and comparable to standard antidepressants, with fewer side effects.
“Nevertheless, many clinical trials have demonstrated efficacy superior to placebo and comparable to standard antidepressants but with fewer side effects than conventional antidepressive agents [367].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [367]
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Premisenone givenCYP2C9 appears to be the most sensitive CYP isoform, with IC50 values around 8 μM for human liver microsomes.
“Of all the CYP isoforms tested, CYP2C9 appears to be the most sensitive with IC 50 values ~8 µM for human liver microsomes.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationSilymarin inhibits the metabolism of losartan to its active metabolite E-3174, and the magnitude of this interaction depends on CYP2C9 genotype.
“More concerning is a recent finding that silymarin inhibits the metabolism of losartan to its active metabolite E-3174, and that the magnitude of the interaction is dependent upon CYP2C9 genotype [364].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [364]
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PremisecitationMost studies agree that flavanolignan concentrations above 10 μM are required to inhibit most CYP isoforms, and even higher concentrations are needed for ABCB1 and ABCG2 inhibition.
“The majority of studies are in general agreement that flavanolignan concentrations in excess of 10 µM are required for inhibition of most CYP isoforms, and even higher concentrations are needed for ABCB1 and ABCG2 inhibition.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisenone givenConcomitant use of St. John's wort and cyclosporine produced dramatic reductions in blood levels of the immunosuppressant among organ transplant recipients, resulting in graft rejection.
“At that time, several clinics around the world reported that concomitant use of SJW and cyclosporine produced dramatic reductions in blood levels of the immunosuppressant among organ transplant recipients resulting in graft rejection.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationReporter gene assays showed that S. chinensis extracts and constituents schisandrin and schisandrol activated rat and human PXR, while certain gomisin H analogues activated phase II detoxification gene expression via Nrf2.
“In contrast, reporter gene assays demonstrated that S. chinensis extracts and its constituents, schisandrin and schisandrol, activated rat and human PXR [310], whereas certain natural gomisin H analogues (e.g., tigloylgomisin H, angeloylgomisin H) significantly activated phase II detoxification gene expression via the Nrf2 nuclear receptor pathway [313].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [310]
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PremisecitationIn healthy adults, 140 mg silymarin for 9 days reduced mean metronidazole AUC by 29%, hinting at possible induction but of little clinical concern.
“In contrast, 140 mg of silymarin administered to healthy adults for 9 days reduced the mean AUC for metronidazole (CYP3A4/ABCB1 substrate) by 29% [363], and while this effect hints at possible induction, it too is of little clinical concern.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [363]
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Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).
Interpretationnone givenThe interaction risk for Schisandra is high.
“Interaction risk: high.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisereasoningComponents of standard milk thistle extracts generally have very low oral bioavailability and short elimination half-lives.
“Components of standard milk thistle extracts, as a general rule, have very low oral bioavailability and short elimination half-lives.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisereasoningThe clinical severity of St. John's wort-mediated interactions was first recognized in 1999-2000.
“As discussed in Part 1 of this review, the clinical severity of SJW-mediated interactions was first recognized in 1999-2000.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationGomisin C inactivation of CYP3A4 was time- and concentration-dependent and irreversible, indicating mechanism-based inhibition.
“In the presence of NADPH, gomisin Cʼs inactivation of CYP3A4 was time-and concentration-dependent, as well as irreversible, characteristics indicative of mechanism-based inhibition.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationcitationSystemic concentrations of silybin and isosilybin diastereomers may be 3-5fold higher in patients with cirrhotic or nonalcoholic fatty liver disease, which may account for milk thistle's purported efficacy in these populations.
“Systemic concentrations of silybin and isosilybin diastereomers may be 3-5fold higher in patients with cirrhotic or nonalcoholic fatty liver disease, which may account for milk thistleʼs purported efficacy in these populations [329,331].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [329]
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InterpretationcitationSpecies differences may stem from humans receiving lower mg/kg doses and from gomisin C concentrations needed for PXR activation in humans being twice those required for murine species.
“Such species differences may stem from the fact that humans not only received lower mg/kg doses of Schisandra, but that gomisin C concentrations necessary for PXR activation in humans are twice those required for murine species [311].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [311]
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PremisecitationHuman PXR is an orphan nuclear receptor expressed selectively in the liver and intestine.
“The prenylated phloroglucinol is a high-affinity ligand for human PXR, an orphan nuclear receptor selectively expressed in the liver and intestine that mediates the induction of XME and efflux transporter gene transcription [375][376][377].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [375]
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PremisecitationNovel formulation technologies include liposomes, self-emulsifying microemulsions, microspheres, phosphatidylcholine complexation (phytosomes), nanoparticles, and piperine as a CYP3A4 and ABCB1 inhibitor.
“Such innovative formulation technologies include liposomes, self-emulsifying microemul-sions, microspheres, phosphatidylcholine complexation (phytosomes), and nanoparticles, as well as the incorporation of piperine as a CYP3A4 and ABCB1 inhibitor [387,388].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [387]
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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone givenHumans have a complex gastrointestinal system of xenobiotic-metabolizing enzymes and transporters that prevents absorption and promotes elimination of many structurally diverse dietary phytochemicals.
“Humans possess a complex system of gastrointestinal XMEs and transporters that are proficient at precluding absorption and facilitating elimination of numerous structurally diverse dietary phytochemicals.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningMDP-PSMs can function as mechanism-based CYP inhibitors and therefore pose significant risks for herb-drug interactions.
“Because MDP-PSMs can function as mechanism-based CYP inhibitors, they pose significant risks for herb-drug interactions.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationInduction of CYPs by MDP-PSMs may be mediated by AhR or by mechanisms that promote protein stabilization.
“Induction of CYPs by MDP-PSMs may be mediated by AhR or through mechanisms that promote protein stabilization [228, 229].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [228]
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- cites [229]
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The paper relies on this without support.
The products and doses used in the cited clinical studies are representative of commercially available botanical supplements when taken as recommended.
“most commercially available garlic supplements pose only a limited risk”
The paper relies on this without support.
Most St. John's wort extracts are currently standardized to contain 3% hyperforin.
“Most SJW extracts are currently standardized to contain 3% hyperforin, yet many brands may possess amounts well below this value.”
The paper relies on this without support.
Many brands of St. John's wort may contain hyperforin amounts well below 3%.
“Most SJW extracts are currently standardized to contain 3% hyperforin, yet many brands may possess amounts well below this value.”
The paper relies on this without support.
Few St. John's wort products are specifically labeled as having low hyperforin content.
“Unfortunately for consumers, few SJW products are specifically labeled as having low hyperforin content.”
The paper relies on this without support.
PXR is polymorphic, and certain mutations produce significant functional defects in CYP3A transcription.
“Like many CYPs, PXR is polymorphic, and certain mutations produce significant functional defects in terms of CYP3A transcription.”
The paper relies on this without support.
Poor dissolution characteristics are major obstacles to phytochemical bioavailability and efficacy.
“Recognizing that poor dissolution characteristics represent major obstacles to phytochemical bioavailability and efficacy, several dietary supplement manufacturers have recently incorporated novel methods of formulating botanical extracts as a means of improving oral absorption [387,388].”
The paper relies on this without support.
No clinical assessments of the herb-drug interaction potential of botanical extracts incorporating novel formulations have been reported to date.
“To date, no clinical assessments of the herb-drug interaction potential of botanical extracts incorporating these novel formulations have been reported.”
The paper relies on this without support.
The vast majority of botanical supplements have not been evaluated in a clinical setting.
“Not surprisingly, the vast majority of these botanicals have yet to be evaluated in a clinical setting.”
The paper relies on this without support.
Hyperforin is a principal mediator of St. John's wort's antidepressive action.
“Hyperforin, a principal mediator of SJWʼs antidepressive action, lies at the heart of the herbʼs drug interaction potential.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Interactions between foods or dietary supplements and drugs are an underappreciated source of therapeutic variability and iatrogenic risk.
“Interactions between foods or dietary supplements and drugs are an underappreciated source of therapeutic variability and iatrogenic risk [1,2].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [2]
The review’s discussion of botanical supplements reports clinically important drug interactions, including reduced drug efficacy with St. John’s wort. Its Black pepper/piperine section also describes altered drug exposure, but says that amounts typically used to flavor food are unlikely to affect most medications. The copy therefore supports interaction-related therapeutic variability and risk for some supplements and food-derived substances, not the broader claim about foods generally or that these interactions are underappreciated (page unavailable). (LLM, conf=0.83)
Experimental — accuracy not yet measuredClinical literature dedicated to berberine interactions remains fragmented, dispersed across isolated pharmacokinetic studies, case reports, and broad pharmacological reviews.
“Nonetheless, the clinical literature dedicated to berberine interactions remains fragmented, dispersed across isolated pharmacokinetic studies, case reports, and broad pharmacological reviews in which interactions are treated only marginally [2,41].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [2]
The Goldenseal section (page unavailable) discusses berberine within a broad review of botanical drug interactions and reports clinical pharmacokinetic findings involving cyclosporine; the References list the individual studies. The paper does not characterize the berberine literature as fragmented or document the claimed spread across case reports and reviews. (LLM, conf=0.82)
Experimental — accuracy not yet measuredNeither direction of product non-conformity can be read off the label, so the defensible position is that the perpetrator dose is unknown.
“Neither direction can be read off the label, so the defensible position is that the perpetrator dose is unknown [2,32,34].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [2]
The ginseng discussion (page unavailable in our copy) reports variability in ginsenoside type and content across products, supporting caution about assuming a consistent amount of an interacting constituent. It does not say that products can deviate from their labels in both directions or that the perpetrator dose must therefore be treated as unknown. (LLM, conf=0.78)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Conflicting descriptions of typical ginkgo study doses
MajorThe paper says the majority of clinical studies used 240 mg twice daily, or 480 mg/day, but later says most human studies used 240 mg/day or less.
“The majority of these studies followed a G. biloba supplementation regimen of 240 mg leaf extract twice daily from as few as 3 to as many as 90 days, while others utilized smaller doses.”
“however, most human studies incorporated doses of 240 mg/day or less.”
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Influence of Piperine on the Pharmacokinetics of Curcumin in Animals and Human Volunteers
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St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor
Moore, L. B., Goodwin, B. J., Jones, S. A., Wisely, G. B., Serabjit‐Singh, C. J., Willson, T. M., Collins, J. L., & Kliewer, S. A. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.130155097 · Cited by 946 · see citing works
Black Pepper and its Pungent Principle-Piperine: A Review of Diverse Physiological Effects
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The Use of Silymarin in the Treatment of Liver Diseases
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Clarifying the real bioactive constituents of garlic
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Flavonoids-potent and versatile biologically active compounds interacting with cytochromes P450
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Applications of novel drug delivery system for herbal formulations
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Ginkgo biloba for cognitive impairment and dementia
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Drug Interaction Studies: Study Design, Data Analysis, and Implications for Dosing and Labeling
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Piperine, a Major Constituent of Black Pepper, Inhibits Human P-glycoprotein and CYP3A4
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Pharmacology of Schisandra chinensis Bail.: An overview of Russian research and uses in medicine
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Cited by
Sorted by citations
Djuv, A., Nilsen, O. G., & Steinsbekk, A. (2013) · BMC Complementary and Alternative Medicine · doi:10.1186/1472-6882-13-295 · Cited by 80 · see citing works
Orellana-Paucar, A., & Vintimilla-Rojas, D. (2020) · Systematic Reviews · doi:10.1186/s13643-019-1259-2 · Cited by 53 · see citing works
Adiwidjaja, J., Boddy, A. V., & McLachlan, A. J. (2022) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-021-03266-y · Cited by 14 · see citing works
Dumitru, C. N., Marcu, T., Dumitru, A. O., Tudor, S. S., Ferțu, I. D., Elisei, A.-M., & Goroftei, L. (2026) · Pharmaceuticals · doi:10.3390/ph19081313 · Cited by 2 · see citing works
“Neither direction can be read off the label, so the defensible position is that the perpetrator dose is unknown [2,32,34].”
Influential
- Authors
- Gurley, B., Fifer, E., & Gardner, Z.
- Affiliations
- University of Arkansas for Medical Sciences (US)
- University of Massachusetts Amherst (US)
- ORCID
- Gurley, Bill
- Venue
- Planta Medica
- Publisher
- Georg Thieme Verlag KG
- Published
- 2012-05-07
- Volume
- 78
- Issue
- 13
- Pages
- 1490-1514
- ISSN
- 0032-0943 (ISSN-L)
- 1439-0221
- OpenAlex
- W1983168442
- Cited by
- 165
- References
- 404
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 7 · 2023: 8 · 2022: 16 · 2021: 10 · 2020: 8 · 2019: 16 · 2018: 16 · 2017: 16 · 2016: 13 · 2015: 15 · 2014: 10 · 2013: 12 · 2012: 1
- FWCI
- 2.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Planta Medica (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Complementary and alternative medicine › Complementary and Alternative Medicine Studies
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Phytochemistry Medicinal Plant Applications
- Keywords
- herb-drug interactions, herbal supplements, cytochrome P450 inhibition, phytochemicals, orphan nuclear receptor, black cohosh, Echinacea, garlic, Ginkgo biloba, ginseng, goldenseal, kava, black pepper, piperine, Schisandra, Silybum marianum, Hypericum perforatum, methylenedioxyphenyl compounds
- MeSH terms
- Adenosine Triphosphate, Cytochrome P-450 Enzyme System, Humans, Pharmacokinetics, Transferases, Dietary Supplements, Magnoliopsida, Membrane Transport Proteins, Plant Preparations, Herb-Drug Interactions
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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