Enhanced Intestinal Absorption and Pharmacokinetic Modulation of Berberine and Its Metabolites through the Inhibition of P-Glycoprotein and Intestinal Metabolism in Rats Using a Berberine Mixed Micelle Formulation
Open accessAbstract
We aimed to develop a berberine formulation to enhance the intestinal absorption and plasma concentrations of berberine through the inhibition of P-glycoprotein (P-gp)-mediated efflux and the intestinal metabolism of berberine in rats. We used pluronic P85 (P85) and tween 80, which have the potential to inhibit P-gp and cytochrome P450s (i.e., CYP1A2, 2C9, 2C19, 2D6, and 3A4). A berberine-loaded mixed micelle formulation with ratios of berberine: P85: tween 80 of 1:5:0.5 (w/w/w) was developed. This berberine mixed micelle formulation had a mean size of 12 nm and increased the cellular accumulation of digoxin via P-gp inhibition. It also inhibited berberine metabolism in rat intestinal microsomes, without significant cytotoxicity, up to a berberine concentration of 100 μM. Next, we compared the pharmacokinetics of berberine and its major metabolites in rat plasma following the oral administration of the berberine formulation (50 mg/kg) in rats with the oral administration of berberine alone (50 mg/kg). The plasma exposure of berberine was significantly greater in rats administered the berberine formulation compared to rats administered only berberine, which could be attributed to the increased berberine absorption by inhibiting the P-gp-mediated berberine efflux and intestinal berberine metabolism by berberine formulation. In conclusion, we successfully prepared berberine mixed micelle formulation using P85 and tween 80 that has inhibitory potential for P-gp and CYPs (CYP2C19, 2D6, and 3A4) and increased the berberine plasma exposure. Therefore, a mixed micelle formulation strategy with P85 and tween 80 for drugs with high intestinal first-pass effects could be applied to increase the oral absorption and plasma concentrations of the drugs.
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The actual berberine content, the presence of co-alkaloids such as hydrastine, the chemical form, and "enhanced-bioavailability" formulations determine the effective perpetrator dose the patient receives.
“The actual berberine content, the presence of co-alkaloids such as hydrastine, the chemical form, and “enhanced-bioavailability” formulations determine the effective perpetrator dose the patient receives [71,109,110].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [109]
Results §3.5 reports that a mixed-micelle formulation increased berberine exposure in rats compared with the same oral berberine dose without the formulation. The paper does not establish how actual product content, hydrastine or other co-alkaloids, or chemical form affect the dose a patient receives; its formulation result is from rats, not patients. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredFormulations designed to raise absorption, whether TPGS-based, dihydroberberine or other enhanced-bioavailability preparations, change systemic exposure deliberately, so an effect size measured with one product cannot be carried over to another even when the labeled dose matches.
“Formulations designed to raise absorption, whether TPGS-based, dihydroberberine or other enhanced-bioavailability preparations, change systemic exposure deliberately, so an effect size measured with one product cannot be carried over to another even when the labeled dose matches.”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [109]
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Sorted by citations
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“For examples, pluronic triblock copolymers such as pluronic F127 and pluronic P85 increased the intestinal permeation of morin and berberine and enhanced their oral bioavailability [47,48].”
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“, 2018), and pluronic P85 and tween 80 (Kwon et al., 2020) to improve the solubility and bioavailability of BBR.”
BackgroundResultBerberine—A Promising Therapeutic Approach to Polycystic Ovary Syndrome in Infertile/Pregnant Women
Ionescu, O.-M., Frîncu, F., Mehedintu, A. M., Plotogea, M., Cîrstoiu, M. M., Petca, A. T., Varlas, V. N., & Mehedințu, C. (2023) · Life · doi:10.3390/life13010125 · Cited by 22 · see citing works
“The intention is to interfere with P-GP-mediated efflux or intestinal metabolism and thus increase berberine plasma levels (Silybum marianum extract, sodium caprate, chitosan, oral microemulsion formulation of BBR, oral microemulsion formulation of BBR, self-micro emulsifying drug delivery system of BBR) [44,45].”
BackgroundWang, X., Fu, L., Cheng, W., Chen, J., Zhang, H., Zhu, H., Zhang, C., Fu, C., Hu, Y., & Zhang, J. (2023) · Drug Delivery · doi:10.1080/10717544.2023.2204207 · Cited by 23 · see citing works
“(Kwon et al., 2020).”
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Self-citationThe Influences and Mechanisms of High-altitude Hypoxia Exposure on Drug Metabolism
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Research progress on antidepressant effects and mechanisms of berberine
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“5 × 104 cells/insert and grown for 5 days with TEER values of over 500 Ω·cm2 [24].”
BackgroundSelf-citationBerberine ameliorates glucocorticoid-induced hyperglycemia: an in vitro and in vivo study
Gupta, M., Rumman, M., Singh, B., Mahdi, A. A., & Pandey, S. (2023) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-023-02703-2 · Cited by 17 · see citing works
“Poor permeability, hepatobiliary re-excretion, P-glycoprotein-mediated efflux, and BBR self-aggregation are the causes of the poor absorption following BBR oral administration (Kwon et al. 2020; Liu et al. 2016).”
Improving the oral bioavailability of berberine: A crystal engineering approach
Surampudi, A. V. S. D., Prasad, S. R., Ramanujam, P., Swain, D., Wadje, B. N., Bharate, S. B., Kamalakannan, U., Kathirvel, M., & Sridhar, B. (2025) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2025.126177 · Cited by 15 · see citing works
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Comparison of Berberine Bioavailability between Oral and Rectal Administrations in Rats
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“…low bioavailability resulting from poor lipid solubility and gastrointestinal absorption, its clinical efficacy via oral administration is limited (Kwon et al. 2020), necessitating consideration of its systemic metabolites when exploring the mechanisms (Yang et al. 2024a; Feng et al. 2020).”
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“Lipid-based carriers with low BA therapeutic drugs could augment intestinal absorption by enhancing the M-cell-mediated uptake, transcellular, and paracellular pathway and by decreasing its efflux mechanism [25,37,38].”
BackgroundSelf-citationChoi, M., Lee, J., & Song, I. (2022) · Journal of Pharmaceutical Investigation · doi:10.1007/s40005-022-00606-7 · Cited by 11 · see citing works
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Berberine-induced browning and energy metabolism: mechanisms and implications
Ağaçdiken, A., & Göktaş, Z. (2025) · PeerJ · doi:10.7717/peerj.18924 · Cited by 8 · see citing works
“This indicates that the inhibition of P-glycoprotein-mediated ef fl ux leads to an increase in the intestinal absorption of berberine ( Kwon et al., 2020 ).”
Bhalodi, K., & Kothari, C. S. (2025) · Microchemical Journal · doi:10.1016/j.microc.2025.114021 · Cited by 8 · see citing works
Dual-trigger release of berberine chloride from the gelatin/perfluorohexane core–shell structure
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“By forming micelles or solubilizing the drug, Tween 80 can enhance the drug’s bioavailability and facilitate its encapsulation within the nanocarrier system (Kwon et al. 2020).”
BackgroundFeng, H., Hong, Y.-J., Zheng, Q.-Q., Ge, J.-M., Cheng, H., Liu, Y., Deng, J., Li, Q., & Qu, S. (2025) · Journal of Colloid and Interface Science · doi:10.1016/j.jcis.2025.138500 · Cited by 6 · see citing works
Beneficial effects of berberine in the treatment of diabetes and its complications
Liu, S., Shen, J., Xu, F., Niu, L., Wang, F., & Zhao, G. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1701513 · Cited by 6 · see citing works
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“Rat Cyp2c11 protein also has 77% homology with human CYP2C9 (Martignoni et al. 2006; Kwon et al. 2020b).”
InfluentialSelf-citationAn in vitro approach to study the absorption of a new oral formulation of berberine
Marino, M., Gardana, C., Scialpi, A., Giorgini, G., Simonetti, P., & Bo’, C. D. (2021) · PharmaNutrition · doi:10.1016/j.phanu.2021.100279 · Cited by 6 · see citing works
Guo, J., Cheng, Y.-P., Lim, C.-J., et al. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15082016 · Cited by 5 · see citing works
“Kwon et al. reported that Pluronic P85 and Tween-80 could inhibit P-glycoprotein and CYP3A4 [15].”
BackgroundKim, J. M., Lee, J., Jeon, S. Y., et al. (2024) · Drug Targets and Therapeutics · doi:10.58502/dtt.24.0008 · Cited by 5 · see citing works
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“Berberine is a natural isoquinoline alkaloid mainly extracted from the rhizomes of Coptidis Rhizoma [1, 2].”
BackgroundWang, J., Lu, S., Zhang, C., Wang, J., Wu, H., & Li, G. (2025) · Drug Design Development and Therapy · doi:10.2147/dddt.s491446 · Cited by 4 · see citing works
“35 Conventional methods to enhance absorption, such as the co-use of absorption enhancers, preparation of phospholipid complexes, or the use of P-gp inhibitors, also cannot significantly increase its bioavailability.”
Jeon, S. Y., Lee, C. H., Lee, J., et al. (2024) · Biotechnology and Bioprocess Engineering · doi:10.1007/s12257-024-00064-y · Cited by 4 · see citing works
“The UDCA-loaded mixed micelles (UDCA-MM) were prepared using poloxamer 407 and polysorbate 80 as previously reported [35, 37].”
Self-citationDemirci, Z., Yeşilay, G., Nalbantoğlu, B., & Bolat, Z. B. (2025) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2025.152473 · Cited by 3 · see citing works
In silico, In vitro, and In vivo Evaluation of the Anti-alzheimer’s Activity of Berberine
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“The supernatant was transferred to autosampler vials and subsequently a 3 µ L aliquot was injected into the LC-MS/MS system [26,28].”
MethodInfluentialSelf-citationDumitru, 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
“Anyone applying the numbers in Tables 1 and 2 should check which preparation generated them [32,41,109,110].”
Inhibitory effects of berberine on Fonsecaea monophora in vitro and in vivo
He, L., Zhu, Y., Mei, X., Yu, B., Lu, S., Mo, D., Fan, R., Chen, X., Liyan, X., & Xie, T. (2025) · BMC Complementary Medicine and Therapies · doi:10.1186/s12906-025-05121-4 · Cited by 1 · see citing works
Song, C., Xu, Q., & Zhao, D. (2026) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2026.121774 · Cited by 1 · see citing works
Preparation of berberine micelles and its anti-skin damage in hyperglycemia mice
Jin, X., Hua, Q., Adu‐Frimpong, M., Li, Q., Wang, Q., Toreniyazov, E., Cao, X., Yu, J., & Xu, X. (2026) · Xenobiotica · doi:10.1080/00498254.2026.2683638 · Cited by 1 · see citing works
“In reference to related literature (Fan et al. 2020; Kwon et al. 2020; Cao et al. 2022), we dissolved berberine (5 mg), F127 (22.5 mg), PLGA (50/50,7000)-PEG (1000)-PLGA (50/50, 7000, 40 mg), and 2% glycyrrhizic acid monoamine salt in proper amount of methanol, and prepared berberine micelles using…”
InfluentialNanotechnology-driven delivery platforms overcoming the bioavailability challenges of berberine
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BERBERINE IN METABOLIC DISORDERS: THE “NATURE’S OZEMPIC” PHENOMENON - A NARRATIVE REVIEW
Lenkiewicz, E., Maciejewska, A., Stepinska, M., Omiecińska, M., Kaczor, M., Trynkiewicz, W., Rybka, Z., Żak, J., Dąbrowska, K., & Winiarczyk, J. (2026) · International Journal of Innovative Technologies in Social Science · doi:10.31435/ijitss.2(50).2026.5247
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“…potential in colitis due to its anti-inflammatory, antimicrobial, antidiarrheal, antioxidant and intestinal barrier-protective properties [8–10]. however, its clinical application is hampered by poor aqueous solubility, low oral bioavailability and rapid efflux by intestinal transporters…”
Nose, M., Tsuge, A., Mizuno, M., et al. (2026) · Journal of Natural Medicines · doi:10.1007/s11418-026-02047-0
“The serum berberine concentration was measured using liq - uid chromatography-tandem mass spectrometry (LC–MS/ MS) based on previous report [10].”
Berberine in oral diseases: molecular mechanisms and therapeutic implications
Wu, S., Wang, B., Zhu, J., et al. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1853738
“…been identified in rat biological samples, including phase I metabolites such as berberrubine, thalifendine, demethyleneberberine, and jatrorrhizine, as well as phase II conjugates such as thalifendine-glucuronide, berberrubine-glucuronide, and thalifendine/berberrubine-sulfate (Kwon et al., 2020).”
InfluentialLiao, Y., Gui, Y., Li, T., Zhou, Q., Chen, X., & Chen, H. (2026) · The American Journal of Chinese Medicine · doi:10.1142/s0192415x26500795
- Authors
- Kwon, M., Lim, D. Y., Lee, C. H., Jeon, J.-H., Choi, M.-K., & Song, I.-S.
- Affiliations
- Kyungpook National University (KR)
- Dankook University (KR)
- Corresponding author
- Choi, Min-Koo
- Song, Im-Sook
- Venue
- Pharmaceutics
- Publisher
- MDPI AG
- Published
- 2020-09-17
- Volume
- 12
- Issue
- 9
- Pages
- 882
- ISSN
- 1999-4923 (ISSN-L)
- PMC
- PMC7558015
- OpenAlex
- W3086056825
- Cited by
- 76
- References
- 46
- Citations by year
- 2026: 13 · 2025: 10 · 2024: 10 · 2023: 19 · 2022: 13 · 2021: 11
- FWCI
- 3.88
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Pharmaceutics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- MSIT (NRF-2020R1A5A2017323 and NRF-2020R1I1A3074384)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Pharmacology › Berberine and alkaloids research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Keywords
- berberine, P-glycoprotein inhibition, intestinal absorption, pharmacokinetics, intestinal metabolism, Pluronic P85, Tween 80, cytochrome P450 inhibition, oral bioavailability, first-pass metabolism
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