Organic cation transporter-mediated drug-drug interaction potential between berberine and metformin

Kwon, Mihwa; Choi, Young A.; Choi, Min-Koo; Song, Im-Sook

doi:10.1007/s12272-014-0510-6

Cited by 56Drug Transport and Resistance MechanismsBerberine and alkaloids researchPharmacogenetics and Drug Metabolism

Organic cation transporter-mediated drug-drug interaction potential between berberine and metformin

Kwon, Mihwa, Choi, Young A., Choi, Min-Koo, Song, Im-Sook·2015·Archives of Pharmacal Research

DOI 10.1007/s12272-014-0510-6

Open this paper in CoChat — free account

Abstract

Berberine, the main active component of the herbal medicine Rhizoma Coptidis, has been reported to have hypoglycemic and insulin-sensitizing effects and, therefore, could be combined with metformin therapy. Thus, we assessed the potential drug-drug interactions between berberine and metformin. We investigated the in vitro inhibitory potency of berberine on metformin uptake in HEK293 cells overexpressing organic cation transporter (OCT) 1 and 2. To investigate whether this inhibitory effect of berberine on OCT1 and OCT2 could change the pharmacokinetics of metformin in vivo, we measured the effect of berberine co-administration on the pharmacokinetics of metformin at a single intravenous dose of 2 mg/kg metformin and 10 mg/kg berberine. In HEK293 cells, berberine inhibited OCT1- and OCT2-mediated metformin uptake in a concentration dependent manner and IC50 values for OCT1 and OCT2 were 7.28 and 11.3 μM, respectively. Co-administration of berberine increased the initial plasma concentration and AUC of metformin and decreased systemic clearance and volume of distribution of metformin in rats, suggesting that berberine inhibited disposition of metformin, which is governed by OCT1 and OCT2. Berberine inhibited the transport activity of OCT1 and OCT2 and showed significant potential drug-drug interactions with metformin in in vivo rats.

Integrity signals

Registry

Crossref · 10.1007/s12272-014-0510-6

Cites

32 of 32 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

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?

OCT1 inhibition by berberine has not been tested directly and remains a mechanistic possibility rather than a documented interaction.
“It has not been tested directly, and we keep it here as a mechanistic possibility rather than a documented interaction [65,82].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [82]
After intravenous administration of metformin, berberine increased exposure and reduced clearance, indicating that the net result reflects the balance between inhibited absorption and inhibited renal secretion.
“The direction of the effect is route-dependent: after intravenous administration of metformin, berberine increased exposure and reduced clearance, indicating that the net result reflects the balance between inhibited absorption and inhibited renal secretion [82].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [82]
Berberine 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 [82]

1 retracted

RETRACTED: Redox Regulation of the AMP-Activated Protein Kinase
Han, Y., Wang, Q., Song, P., Zhu, Y., & Zou, M.-H. (2010) · PLoS ONE · doi:10.1371/journal.pone.0015420 · Cited by 71 · see citing works
Retracted
Membrane transporters in drug development
The International Transporter Consortium, Giacomini, K. M., Huang, S.-M., Tweedie, D. J., Benet, L. Z., Brouwer, K. L. R., Chu, X., Dahlin, A., Evers, R., Fischer, V., et al. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd3028 · Cited by 3,340 · see citing works
Polyspecific Organic Cation Transporters: Structure, Function, Physiological Roles, and Biopharmaceutical Implications
Koepsell, H., Lips, K. S., & Volk, C. (2007) · Pharmaceutical Research · doi:10.1007/s11095-007-9254-z · Cited by 984 · see citing works
Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action
Shu, Y., Sheardown, S. A., Brown, C., Owen, R., Zhang, S., Castro, R. A., Ianculescu, A. G., Lin, Y., Lo, J. C.-M., Burchard, E. G., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30558 · Cited by 963 · see citing works
Efficacy of berberine in patients with type 2 diabetes mellitus
Yin, J., Xing, H., & Ye, J. (2008) · Metabolism · doi:10.1016/j.metabol.2008.01.013 · Cited by 801 · see citing works
Treatment of Type 2 Diabetes and Dyslipidemia with the Natural Plant Alkaloid Berberine
Zhang, Y., Li, X., Zou, D., Liu, W., Yang, J., Zhu, N., Huo, L., Wang, M., Hong, J., Wu, P., et al. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-2404 · Cited by 573 · see citing works
Metformin kinetics in healthy subjects and in patients with diabetes mellitus.
Tucker, G., Casey, C., Phillips, P., Connor, H., Ward, J. D., & Woods, H. (1981) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.1981.tb01206.x · Cited by 497 · see citing works
Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression
Zhang, H., Wei, J., Xue, R., Wu, J.-D., Zhao, W., Wang, Z., Wang, S., Zhou, Z.-X., Song, D., Wang, Y., et al. (2009) · Metabolism · doi:10.1016/j.metabol.2009.07.029 · Cited by 442 · see citing works
Organic cation transporters are determinants of oxaliplatin cytotoxicity.
Zhang, S., Lovejoy, K. S., Shima, J. E., Lagpacan, L. L., Shu, Y., Lapuk, A., Chen, Y., Komori, T., Gray, J., Chen, X., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-0769 · Cited by 426 · see citing works
Extensive intestinal first-pass elimination and predominant hepatic distribution of berberine explain its low plasma levels in rats
Liu, Y.-T., Hao, H.-P., Xie, H.-G., Lai, L., Wang, Q., Liu, C.-X., & Wang, G.-J. (2010) · Drug Metabolism and Disposition · doi:10.1124/dmd.110.033936 · Cited by 356 · see citing works
Berberine in the treatment of type 2 diabetes mellitus: A systemic review and meta-analysis
Dong, H., Wang, N., Zhao, L., & Lu, F. (2012) · Evidence-Based Complementary and Alternative Medicine · doi:10.1155/2012/591654 · Cited by 225 · see citing works
Involvement of Organic Cation Transporter 1 in the Lactic Acidosis Caused by Metformin
Wang, D., Kusuhara, H., Kato, Y., Jonker, J. W., Schinkel, A. H., & Sugiyama, Y. (2003) · Molecular Pharmacology · doi:10.1124/mol.63.4.844 · Cited by 193 · see citing works
Determination of berberine in human plasma by liquid chromatography–electrospray ionization–mass spectrometry
Hua, W., Ding, L., Chen, Y., Gong, B., He, J., & Xu, G. (2007) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2007.03.022 · Cited by 192 · see citing works
Synergistic effect of phytochemicals in combination with hypoglycemic drugs on glucose uptake in myotubes
Prabhakar, P. K., & Doble, M. (2009) · Phytomedicine · doi:10.1016/j.phymed.2009.05.021 · Cited by 179 · see citing works
Measurement of the renal clearance of drugs.
Tucker, G. (1981) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.1981.tb01304.x · Cited by 176 · see citing works
Berberine-induced AMPK activation inhibits the metastatic potential of melanoma cells via reduction of ERK activity and COX-2 protein expression
Kim, H.-S., Kim, M.-J., Kim, E. J., Yang, Y. D., Lee, M., & Lim, J. (2011) · Biochemical Pharmacology · doi:10.1016/j.bcp.2011.11.008 · Cited by 175 · see citing works
Hypoglycemic and insulin-sensitizing effects of berberine in high-fat diet- and streptozotocin-induced diabetic rats
Wang, Y., Campbell, T., Perry, B., Beaurepaire, C., & Qin, L. (2010) · Metabolism · doi:10.1016/j.metabol.2010.02.005 · Cited by 140 · see citing works
Repeated administration of berberine inhibits cytochromes P450 in humans
Guo, Y., Chen, Y., Tan, Z.-R., Klaassen, C. D., & Zhou, H.-H. (2012) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-011-1108-2 · Cited by 137 · see citing works
Development of the “Inje Cocktail” for High-throughput Evaluation of Five Human Cytochrome P450 Isoforms in vivo
Ryu, J. Y., Song, I., Sunwoo, Y. E., SHON, J., Liu, K. H., Cha, I., & Shin, J. (2007) · Clinical Pharmacology & Therapeutics · doi:10.1038/sj.clpt.6100187 · Cited by 129 · see citing works
Self-citation
Dose-Independent Pharmacokinetics of Metformin in Rats: Hepatic and Gastrointestinal First-Pass Effects
Choi, Y. H., Kim, S. G., & Lee, M. G. (2006) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.20744 · Cited by 129 · see citing works
Self-citation
Vectorial transport of the plant alkaloid berberine by double-transfected cells expressing the human organic cation transporter 1 (OCT1, SLC22A1) and the efflux pump MDR1 P-glycoprotein (ABCB1)
Nies, A. T., Herrmann, E., Brom, M., & KEPPLER, D. O. R. (2007) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-007-0219-x · Cited by 124 · see citing works
Organic cation transporters and their pharmacokinetic and pharmacodynamic consequences.
Choi, M., & Song, I. (2008) · Drug Metabolism and Pharmacokinetics · doi:10.2133/dmpk.23.243 · Cited by 118 · see citing works
Self-citation
Berberine improves insulin resistance in cardiomyocytes via activation of 5′-adenosine monophosphate-activated protein kinase
Chang, W., Zhang, M., Li, J., Meng, Z., Wei, S., Du, H., Chen, L., & Hatch, G. M. (2013) · Metabolism · doi:10.1016/j.metabol.2013.02.007 · Cited by 102 · see citing works
Metformin suppresses pregnane X receptor (PXR)-regulated transactivation of CYP3A4 gene
Krausová, L., Stejskalová, L., Wang, H., Vrzal, R., Dvořák, Z., Mani, S., & Pávek, P. (2011) · Biochemical Pharmacology · doi:10.1016/j.bcp.2011.08.023 · Cited by 96 · see citing works
Effects of berberine on the blood concentration of cyclosporin A in renal transplanted recipients: Clinical and pharmacokinetic study
Wu, X., Li, Q., Xin, H., Yu, A., & Zhong, M. (2005) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-005-0952-3 · Cited by 90 · see citing works
Berberine modulates insulin signaling transduction in insulin-resistant cells
Liu, L., Cheung, S. C. K., Lan, L., Ho, S. K. S., Xu, H., Chan, J. C. N., & Tong, P. C. Y. (2009) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2009.12.027 · Cited by 74 · see citing works
Effects of enzyme inducers and inhibitors on the pharmacokinetics of metformin in rats: involvement of CYP2C11, 2D1 and 3A1/2 for the metabolism of metformin
Choi, Y. H., & Lee, M. G. (2006) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706875 · Cited by 58 · see citing works
Self-citation
Reduced Antidiabetic Effect of Metformin and Down-regulation of Hepatic Oct1 in Rats with Ethynylestradiol-Induced Cholestasis
Jin, H., Hong, S., Choi, M., Maeng, H., Kim, D., Chung, S., & Shim, C. (2008) · Pharmaceutical Research · doi:10.1007/s11095-008-9770-5 · Cited by 52 · see citing works
Self-citation
The <i>In Vitro</i> Inhibition of Human CYP1A2, CYP2D6 and CYP3A4 by Tetrahydropalmatine, Neferine and Berberine
Zhao, Y., Hellum, B. H., Liang, A., & Nilsen, O. G. (2012) · Phytotherapy Research · doi:10.1002/ptr.3554 · Cited by 51 · see citing works
Pharmacokinetic interaction between itraconazole and metformin in rats: competitive inhibition of metabolism of each drug by each other via hepatic and intestinal CYP3A1/2
Choi, Y. H., Lee, U., Lee, B., et al. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.00913.x · Cited by 47 · see citing works
Self-citation
Effects of tetraalkylammonium compounds with different affinities for organic cation transporters on the pharmacokinetics of metformin
Choi, M., Jin, Q., Jin, H., Shim, C., Cho, D., Shin, J., & Song, I. (2007) · Biopharmaceutics & Drug Disposition · doi:10.1002/bdd.576 · Cited by 36 · see citing works
Self-citation
molecular pharmaceutics
(2003) · Chemical & Engineering News · doi:10.1021/cen-v081n041.p116 · Cited by 22 · see citing works

Flagged first, then by citations

Sorted by citations

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
Kwon, M., Lim, D. Y., Lee, C. H., Jeon, J.-H., Choi, M.-K., & Song, I.-S. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12090882 · Cited by 76 · see citing works
“Berberine (Figure 1), an isoquinoline alkaloid isolated from Coptidis Rhizoma, has long been used as a folklore remedy in China for the treatment of bacteria-associated diarrhea and other gastrointestinal infections [1].”
BackgroundSelf-citation
Pharmacokinetics and Pharmacological Activities of Berberine in Diabetes Mellitus Treatment
Han, Y., Xiang, Y., Shi, Y., Tang, X., Pan, L., Gao, J., Bi, R., & Lai, X. (2021) · Evidence-Based Complementary and Alternative Medicine · doi:10.1155/2021/9987097 · Cited by 51 · see citing works
Biodistribution and pharmacokinetic profile of berberine and its metabolites in hepatocytes
Liu, X., Li, W., Zhang, H., Wang, X., Huang, Y., Li, Y., & Pan, G. (2022) · Phytomedicine · doi:10.1016/j.phymed.2022.154288 · Cited by 27 · see citing works
Organic cation transporter and multidrug and toxin extrusion 1 co-mediated interaction between metformin and berberine
Shi, R., Xu, Z., Xu, X., Jin, J., Zhao, Y., Wang, T., Li, Y., & Ma, Y. (2019) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2018.11.010 · Cited by 25 · see citing works
Sex‐Dependent Effects of <scp>CYP2D6</scp> on the Pharmacokinetics of Berberine in Humans
Blöcher, J. A., Meyer‐Tönnies, M. J., Morof, F., Rönnpagel, V., Bethmann, J., Vollmer, M., Engeli, S., & Tzvetkov, M. V. (2025) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.3454 · Cited by 16 · see citing works
Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review
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
“Cyclosporine CYP3A4 + P-gp inhibition [36,80] ↑ exposure (AUC +34.5%; Cmin +29.3% vs. control) [118] A—controlled clinical study in patients (renal transplant) [117,118] Tacrolimus, sirolimus CYP3A4 + P-gp inhibition [58,80] ↑ exposure (sirolimus preclinical; tacrolimus extrapolated) C—in vivo preclinical (sirolimus);…”
Influential

Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action
Shu, Y., Sheardown, S. A., Brown, C., Owen, R., Zhang, S., Castro, R. A., Ianculescu, A. G., Lin, Y., Lo, J. C.-M., Burchard, E. G., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30558 · Cited by 963 · see citing works
The relationship between OCT gene polymorphism and metformin therapeutic effects
Li, Q., & Liu, F. (2009) · Intern J Endocrinol Metab · doi:10.3760/cma.j.issn.1673-4157.2009.06.008
The role of organic cation transporters in the pharmacokinetics and pharmacodynamics of metformin
Chen, E. C.-T. (2015) · eScholarship (California Digital Library)
OATs and OCTs: The SLC22 Family of Organic Anion and Cation Transporters
Matsson, P., & Karlgren, M. (2021) · Royal Society of Chemistry eBooks · doi:10.1039/9781788016414-00128
Renoprotective Effects of Metformin are Independent of Organic Cation Transporters 1 & 2 and AMP-activated Protein Kinase in the Kidney
Christensen, M. S., Jensen, J., Jakobsen, S., Jessen, N., Frøkiær, J., Kemp, B. E., Marciszyn, A. L., Li, H., Pastor‐Soler, N. M., Hallows, K. R., et al. (2016) · Scientific Reports · doi:10.1038/srep35952 · Cited by 37 · see citing works

Authors: Kwon, M., Choi, Y. A., Choi, M.-K., & Song, I.-S.
Affiliations: Kyungpook National University (KR)
Dankook University (KR)
Corresponding author: Song, Im-Sook
ORCID: Choi, Min-Koo
Song, Im-Sook
Venue: Archives of Pharmacal Research
Publisher: Springer Science and Business Media LLC
Published: 2014-10-31
Volume: 38
Issue: 5
Pages: 849-856
ISSN: 0253-6269 (ISSN-L)
1976-3786
DOI: 10.1007/s12272-014-0510-6
OpenAlex: W2094140987
Cited by: 56
References: 32
Citations by year: 2026: 4 · 2025: 4 · 2024: 7 · 2023: 3 · 2022: 5 · 2021: 5 · 2020: 2 · 2019: 5 · 2018: 5 · 2017: 2 · 2016: 8 · 2015: 6
FWCI: 2.57
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Archives of Pharmacal Research (publishedVersion)
PubMed (publishedVersion)
Funders: Kyungpook National University
Topics: Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Health Sciences › Medicine › Pharmacology › Berberine and alkaloids research
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords: berberine, metformin, drug-drug interactions, OCT1, organic cation transporter 2, Coptidis Rhizoma, herbal medicine, drug transport inhibition
MeSH terms: Organic Cation Transporter 2, Animals, Berberine, Drug Interactions, Humans, Male, Metformin, Rats, Sprague-Dawley, Organic Cation Transport Proteins, Catecholamine Plasma Membrane Transport Proteins, Rats, HEK293 Cells, Administration, Intravenous

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.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Organic cation transporter-mediated drug-drug interaction potential between berberine and metformin

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Cites

Cited by

Related

Record

About these checks