Assessing Transporter‐Mediated Natural Product‐Drug Interactions Via In vitro ‐ In Vivo Extrapolation: Clinical Evaluation With a Probe Cocktail
Open accessAbstract
The botanical natural product goldenseal can precipitate clinical drug interactions by inhibiting cytochrome P450 (CYP) 3A and CYP2D6. Besides P‐glycoprotein, effects of goldenseal on other clinically relevant transporters remain unknown. Established transporter‐expressing cell systems were used to determine the inhibitory effects of a goldenseal extract, standardized to the major alkaloid berberine, on transporter activity. Using recommended basic models, the extract was predicted to inhibit the efflux transporter BCRP and uptake transporters OATP1B1/3. Using a cocktail approach, effects of the goldenseal product on BCRP, OATP1B1/3, OATs, OCTs, MATEs, and CYP3A were next evaluated in 16 healthy volunteers. As expected, goldenseal increased the area under the plasma concentration‐time curve (AUC 0–inf ) of midazolam (CYP3A; positive control), with a geometric mean ratio (GMR) (90% confidence interval (CI)) of 1.43 (1.35–1.53). However, goldenseal had no effects on the pharmacokinetics of rosuvastatin (BCRP and OATP1B1/3) and furosemide (OAT1/3); decreased metformin (OCT1/2, MATE1/2‐K) AUC 0–inf (GMR, 0.77 (0.71–0.83)); and had no effect on metformin half‐life and renal clearance. Results indicated that goldenseal altered intestinal permeability, transport, and/or other processes involved in metformin absorption, which may have unfavorable effects on glucose control. Inconsistencies between model predictions and pharmacokinetic outcomes prompt further refinement of current basic models to include differential transporter expression in relevant organs and intestinal degradation/metabolism of the precipitant(s). Such refinement should improve in vitro ‐ in vivo prediction accuracy, contributing to a standard approach for studying transporter‐mediated natural product‐drug interactions.
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In a probe-cocktail study in 16 healthy volunteers, a goldenseal extract standardized to berberine reduced metformin systemic exposure while increasing midazolam AUC (geometric mean ratio 1.43; 90% CI 1.35-1.53).
“Clinical support comes from a probe-cocktail study in 16 healthy volunteers, in which a goldenseal extract standardized to berberine reduced metformin systemic exposure while increasing midazolam AUC (geometric mean ratio 1.43; 90% CI 1.35–1.53) [83].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [83]
The Clinical study methods and Results (pages not provided) support the 16-volunteer probe-cocktail study, the decrease in metformin exposure, and the midazolam AUC ratio of 1.43 (90% CI 1.35–1.53). But the methods distinguish the goldenseal product given to volunteers from the extract standardized to berberine for in vitro testing; the claim incorrectly describes the clinical treatment as that standardized extract. (LLM, conf=0.90)
Experimental — accuracy not yet measuredBerberine has a bidirectional interaction with metformin, a prototypical substrate of OCT/MATE transporters.
“This mechanism underlies a bidirectional interaction with metformin, a prototypical substrate of these transporters.”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [83]
The Discussion (page unavailable) reports that goldenseal co-administration reduced metformin exposure and identifies berberine as a potential contributor to transporter inhibition. It does not establish a bidirectional berberine–metformin interaction: the reported clinical effect is goldenseal on metformin, while ‘bidirectionality’ refers to OCT transport in enterocytes. (LLM, conf=0.85)
Experimental — accuracy not yet measuredAcross the whole field, the paper identified one controlled study in patients (renal-transplant recipients receiving cyclosporine), one probe-cocktail study in healthy volunteers, and one human enzyme-phenotyping study; everything else is preclinical, in vitro or observational.
“Across the whole field we identified one controlled study in patients, in renal-transplant recipients receiving cyclosporine, one probe-cocktail study in healthy volunteers, and one human enzyme-phenotyping study; everything else is preclinical, in vitro or observational.”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [83]
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredA synthesis resting on three human studies cannot support strong statements about effect size in practice, whatever the mechanistic literature suggests.
“A synthesis resting on three human studies cannot support strong statements about effect size in practice, whatever the mechanistic literature suggests [35,83,118].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [83]
The Discussion (page unavailable) reports discrepancies between in vitro model predictions and clinical pharmacokinetic outcomes, supporting caution about relying on mechanistic evidence alone. The paper reports its own clinical study, however; it does not assess a synthesis of three human studies or say what effect size that evidence can establish in practice. (LLM, conf=0.78)
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“In the terms set out in Section 3 this is the one transporter-mediated pair that passes beyond mechanistic status: it is documented in animals and, for systemic exposure, in a human probe study [65,82,83].”
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Self-citationCombination of drug therapy and membrane-modified exosomes for the treatment of rheumatoid arthritis
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Self-citation
- Authors
- Nguyen, J. T., Tian, D., Tanna, R. S., Hadi, D. L., Bansal, S., Calamia, J. C., Arian, C. M., Shireman, L. M., Molnár, B., Horváth, M., Kellogg, J. J., Layton, M. E., White, J. R., Cech, N. B., Boyce, R. D., Unadkat, J. D., Thummel, K. E., & Paine, M. F.
- Affiliations
- Washington State University Spokane (US)
- Department of Pharmaceutical Sciences College of Pharmacy and Pharmaceutical Sciences Washington State University Spokane Washington USA
- University of Washington (US)
- University of Szeged (HU)
- University of North Carolina at Greensboro (US)
- University of Pittsburgh (US)
- Corresponding author
- Paine, Mary F.
- ORCID
- Venue
- Clinical Pharmacology & Therapeutics
- Publisher
- Wiley
- Published
- 2020-12-23
- Volume
- 109
- Issue
- 5
- Pages
- 1342-1352
- ISSN
- 0009-9236 (ISSN-L)
- 1532-6535
- PMC
- PMC8058163
- OpenAlex
- W3103924104
- Cited by
- 40
- References
- 45
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 10 · 2023: 9 · 2022: 8 · 2021: 1
- FWCI
- 1.62
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Office of Dietary Supplements (U54 AT008909‐06)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Complementary and alternative medicine › Complementary and Alternative Medicine Studies
- Keywords
- goldenseal, berberine, transporter inhibition, in vitro-in vivo extrapolation, ABCG2, OATP1B1, OATP1B3, P-glycoprotein, CYP3A, intestinal absorption, midazolam, rosuvastatin, furosemide
- MeSH terms
- Rosuvastatin Calcium, Adult, Alkaloids, Biological Products, Drug Evaluation, Female, Furosemide, Humans, Male, Metformin, Midazolam, Plant Extracts, Cross-Over Studies, Organic Anion Transporters, Organic Cation Transport Proteins, Hydrastis, Herb-Drug Interactions, HEK293 Cells
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