Sex‐Dependent Effects of CYP2D6 on the Pharmacokinetics of Berberine in Humans
Open accessAbstract
An over‐the‐counter product berberine (a major alkaloid in goldenseal) is a substrate of the uptake transporter OCT1 and the metabolizing enzyme CYP2D6. The two genes exhibit common functional polymorphisms. Approximately 9% of Europeans and white Americans are either poor CYP2D6 metabolizers or poor OCT1 transporters. In this study, we investigated the effects of OCT1 and CYP2D6 polymorphisms on berberine pharmacokinetics in humans. We confirmed in vitro that berberine is an OCT1 substrate ( K M of 7.0 μM, CL int of 306 ± 29 μL/min/mg). Common OCT1 alleles *3 to *6 showed uptake reduced by at least 65% and Oct1/2 knockout mice showed 3.2‐fold higher AUCs in liver perfusion experiments. However, in humans, poor OCT1 transporters did not show any differences in berberine pharmacokinetics compared with reference participants. In contrast, CYP2D6 polymorphisms significantly affected berberine metabolism, but exclusively in females. Females who were poor CYP2D6 metabolizers had an 80% lower M1‐to‐berberine ratio. General linear model analyses suggest strong synergistic, rather than additive, effects between female sex and CYP2D6 genotype. Overall, berberine displayed low oral bioavailability, yet females had a 2.8‐fold higher AUC and a 3.6‐fold higher C max than males ( P < 0.001). These effects were only partially attributable to the sex‐ CYP2D6 genotype interaction. In conclusion, despite berberine being an OCT1 substrate, OCT1 deficiency did not affect berberine pharmacokinetics in humans. In contrast, CYP2D6 emerges as a critical enzyme for berberine metabolism in females, but not in males, highlighting sex‐specific differences. We suggest that factors beyond CYP2D6 metabolism are determining berberine's systemic exposure, especially in males (NCT05463003).
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CYP2D6, together with CYP1A2, is a main metabolizing pathway of berberine itself; CYP2D6 polymorphism and sex-related differences influence berberine exposure.
“This CYP2D6 relevance is reinforced by the fact that this isoenzyme, together with CYP1A2, is also the main metabolizing pathway of berberine itself; CYP2D6 polymorphism and sex-related differences influence berberine exposure, adding a source of interindividual variability in the magnitude of interactions [70].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [70]
The Abstract reports sex differences in berberine exposure and an effect of CYP2D6 polymorphism on metabolism, but the latter was observed only in females. The Discussion says CYP1A2 is a possible compensating enzyme in males, not an established main pathway alongside CYP2D6; it also says CYP2D6 deficiency changed metabolite-to-berberine ratios but not berberine AUC. The paper does not establish that these differences change the magnitude of drug interactions. (LLM, conf=0.87)
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Cites
Measurement of protein using bicinchoninic acid
Smith, P. K., Krohn, R. I., Hermanson, G. T., Mallia, A. K., Gartner, F. H., Provenzano, M. D., Fujimoto, E. K., Goeke, N. M., Olson, B. J., & Klenk, D. C. (1985) · Analytical Biochemistry · doi:10.1016/0003-2697(85)90442-7 · Cited by 18,482 · see citing works
A new collection method for the evaluation of nasal mucus proteins
Ruocco, L. A., Fattori, Romanelli, Martelloni, L., Casani, Samolewska, & Rezzonico (1998) · Clinical & Experimental Allergy · doi:10.1046/j.1365-2222.1998.00312.x · Cited by 1,296 · 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 971 · see citing works
Current knowledge and pharmacological profile of berberine: An update
Kumar, A., Ekavali, Chopra, K., Mukherjee, M., Pottabathini, R., & Dhull, D. K. (2015) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2015.05.068 · Cited by 533 · see citing works
Berberine in Cardiovascular and Metabolic Diseases: From Mechanisms to Therapeutics
Feng, X., Sureda, A., Jafari, S., Memariani, Z., Tewari, D., Annunziata, G., Barrea, L., Hassan, S. T. S., Šmejkal, K., Malaník, M., et al. (2019) · Theranostics · doi:10.7150/thno.30787 · Cited by 465 · see citing works
Nies, A. T., Koepsell, H., Winter, S., Burk, O., Klein, K., Kerb, R., Zanger, U. M., KEPPLER, D. O. R., Schwab, M. G., & Schaeffeler, E. (2009) · Hepatology · doi:10.1002/hep.23103 · Cited by 382 · see citing works
Chen, W., Miao, Y.-Q., Fan, D.-J., Yang, S.-S., Lin, X., Meng, L.-K., & Tang, X. (2011) · AAPS PharmSciTech · doi:10.1208/s12249-011-9632-z · Cited by 363 · see citing works
Shu, Y., Leabman, M. K., Feng, B., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0730858100 · Cited by 286 · see citing works
GURLEY, B., GARDNER, S., HUBBARD, M., WILLIAMS, D., GENTRY, W., KHAN, I., & SHAH, A. (2005) · Clinical Pharmacology & Therapeutics · doi:10.1016/j.clpt.2005.01.009 · Cited by 271 · see citing works
Jonker, J., Wagenaar, E., van Eijl, S., & Schinkel, A. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.21.7902-7908.2003 · Cited by 270 · see citing works
Battu, S. K., Repka, M. A., Maddineni, S., Chittiboyina, A. G., Avery, M. A., & Majumdar, S. (2010) · AAPS PharmSciTech · doi:10.1208/s12249-010-9520-y · Cited by 261 · see citing works
Nofziger, C., Turner, A., Sangkuhl, K., et al. (2019) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.1643 · Cited by 242 · see citing works
Chen, L., Shu, Y., Liang, X., Chen, E. C., Yee, S. W., Zur, A. A., Li, S., Xu, L., Keshari, K. R., Lin, M. J., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1314939111 · Cited by 234 · see citing works
Biological Activity of Berberine—A Summary Update
Och, A., Podgórski, R., & Nowak, R. (2020) · Toxins · doi:10.3390/toxins12110713 · Cited by 223 · see citing works
Bell, G., Caudle, K., Whirl‐Carrillo, M., et al. (2016) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.598 · Cited by 219 · see citing works
Kerb, R., Brinkmann, U., Chatskaia, N., et al. (2002) · Pharmacogenetics · doi:10.1097/00008571-200211000-00002 · Cited by 214 · see citing works
Tzvetkov, M. V., Pereira, J. N. S., Meineke, I., Saadatmand, A. R., Stingl, J., & Brockmöller, J. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.06.019 · Cited by 206 · see citing works
Self-citationSex differences in genetic architecture in the UK Biobank
Bernabeu, E., Canela‐Xandri, O., Rawlik, K., Talenti, A., Prendergast, J. G. D., & Tenesa, A. (2021) · Nature Genetics · doi:10.1038/s41588-021-00912-0 · Cited by 206 · see citing works
Sex-specific differences in CYP450 isoforms in humans
Scandlyn, M. J., Stuart, E. C., & Rosengren, R. J. (2008) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.4.4.413 · Cited by 199 · see citing works
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
Gurley, B. J., Swain, A., Hubbard, M. A., Williams, D. K., Barone, G., Hartsfield, F., Tong, Y., Carrier, D. J., Cheboyina, S., & Battu, S. K. (2008) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.200600300 · Cited by 169 · see citing works
Evaluation of probe drugs and pharmacokinetic metrics for CYP2D6 phenotyping
Frank, D., Jaehde, U., & Fuhr, U. (2007) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-006-0250-8 · Cited by 164 · see citing works
Race and Sex Differences of Long-Term Blood Pressure Profiles From Childhood and Adult Hypertension
Shen, W., Zhang, T., Li, S., Zhang, H., Xi, B., Shen, H., Fernandez, C., Bazzano, L., He, J., & Chen, W. (2017) · Hypertension · doi:10.1161/hypertensionaha.117.09537 · Cited by 135 · see citing works
Pharmacokinetics and Excretion of Berberine and Its Nine Metabolites in Rats
Feng, X., Wang, K., Cao, S., Ding, L., & Qiu, F. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.594852 · Cited by 130 · see citing works
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
Droździk, M., Busch, D., Lapczuk, J., Müller, J., Ostrowski, M., Kurzawski, M., & Oswald, S. (2019) · Clinical pharmacology and therapy · doi:10.1002/cpt.1301 · Cited by 123 · see citing works
Impact of Smoking, Smoking Cessation, and Genetic Polymorphisms on CYP1A2 Activity and Inducibility
Dobrinas, M., Cornuz, J., Oneda, B., Serra, M. K., Puhl, M., & Eap, C. B. (2011) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2011.70 · Cited by 117 · see citing works
Ezzet, F., Krishna, G., Wexler, D. B., Statkevich, P., Kosoglou, T., & Batra, V. K. (2001) · Clinical Therapeutics · doi:10.1016/s0149-2918(01)80075-8 · Cited by 116 · see citing works
Seitz, T., Stalmann, R., Dalila, N., Chen, J., Pojar, S., Pereira, J. N. S., Krätzner, R., Brockmöller, J., & Tzvetkov, M. V. (2015) · Genome Medicine · doi:10.1186/s13073-015-0172-0 · Cited by 113 · see citing works
Self-citationMatthaei, J., Kuron, D., Faltraco, F., et al. (2015) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.317 · Cited by 98 · see citing works
CYP2D plays a major role in berberine metabolism in liver of mice and humans
Guo, Y., Li, F., Ma, X., Cheng, X., Zhou, H., & Klaassen, C. D. (2011) · Xenobiotica · doi:10.3109/00498254.2011.597456 · Cited by 86 · see citing works
Saadatmand, A. R., Tadjerpisheh, S., Brockmöller, J., et al. (2012) · Biochemical Pharmacology · doi:10.1016/j.bcp.2012.01.032 · Cited by 71 · see citing works
Kashuba, A. D. M., Nafziger, A. N., KEARNS, G., et al. (1998) · Pharmacogenetics · doi:10.1097/00008571-199810000-00005 · Cited by 71 · see citing works
Tzvetkov, M. V., Matthaei, J., Pojar, S., et al. (2017) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.812 · Cited by 71 · see citing works
Self-citationAlolga, R. N., Fan, Y., Chen, Z., Liu, L., Zhao, Y., Li, J., Chen, Y., Lai, M., Li, P., & Qi, L. (2016) · Scientific Reports · doi:10.1038/srep27671 · Cited by 57 · see citing works
Effects of genetic polymorphisms on the OCT1 and OCT2-mediated uptake of ranitidine
Meyer, M. J., Seitz, T., Brockmöller, J., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0189521 · Cited by 57 · see citing works
Organic cation transporter-mediated drug-drug interaction potential between berberine and metformin
Kwon, M., Choi, Y. A., Choi, M.-K., & Song, I.-S. (2015) · Archives of Pharmacal Research · doi:10.1007/s12272-014-0510-6 · Cited by 56 · see citing works
Solnier, J., Zhang, Y., Kuo, Y., Du, M., Roh, K., Gahler, R., Wood, S., & Chang, C. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15112567 · Cited by 47 · see citing works
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., et al. (2021) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.2107 · Cited by 40 · see citing works
Matthaei, J., Tzvetkov, M. V., Strube, J., Sehrt, D. B., Sachse-Seeboth, C., Hjelmborg, J., Möller, S., Halekoh, U., Hofmann, U., Schwab, M. G., et al. (2016) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.444 · Cited by 38 · see citing works
Self-citationSex Differences in Associations Between CYP2D6 Phenotypes and Response to Opioid Analgesics
Lopes, G. S., Bielinski, S. J., Moyer, A. M., et al. (2020) · Pharmacogenomics and Personalized Medicine · doi:10.2147/pgpm.s239222 · Cited by 36 · see citing works
Paine, M. F., Shen, D. D., & McCune, J. S. (2018) · Drug Metabolism and Disposition · doi:10.1124/dmd.117.079962 · Cited by 35 · see citing works
Doetsch, D. A., Ansari, S., Jensen, O., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23158430 · Cited by 28 · see citing works
The mystery of the human proton-organic cation antiporter: One transport protein or many?
Sachkova, A., Jensen, O., Dücker, C., Ansari, S., & Brockmöller, J. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108283 · Cited by 25 · see citing works
Vay, M., Meyer, M. J., Blank, A., et al. (2020) · Clinical Pharmacokinetics · doi:10.1007/s40262-020-00862-6 · Cited by 17 · see citing works
Nguyen, J. T., Tian, D., Tanna, R. S., Arian, C. M., Calamia, J. C., Rettie, A. E., Thummel, K. E., & Paine, M. F. (2023) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.123.001681 · Cited by 13 · see citing works
Yağız, Y., Wang, G. P., & Gu, L. (2022) · Food & Function · doi:10.1039/d2fo02288e · Cited by 5 · see citing works
Oyanna, V. O., Garcia-Torres, K. Y., Bechtold, B. J., Lynch, K. D., Call, M. R., Horváth, M., Manwill, P. K., Graf, T. N., Cech, N. B., Oberlies, N. H., et al. (2023) · Drug Metabolism and Disposition · doi:10.1124/dmd.123.001360 · Cited by 5 · see citing works
Combined and independent effects of OCT1 and CYP2D6 on the cellular disposition of drugs
Gebauer, L., Dücker, C., Jensen, O., et al. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114454 · Cited by 4 · see citing works
Meyer, M. J., Falk, S., Römer, S., Prinzinger, C., Tacke, S., Geyer, J., Simm, S., & Tzvetkov, M. V. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23095100 · Cited by 3 · see citing works
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- [38]Gaither, K.A. et al. Effects of alcohol consumption and tobacco smoking on the composition of the ensemble of drug metabolizing enzymes and transporters in human liver. bioRxiv (2024). https://www.biorxiv.org/content/biorxiv/early/2024/05/17/2024.05.14.594255.full.pdf.
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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
- Authors
- Blöcher, J. A., Meyer‐Tönnies, M. J., Morof, F., Rönnpagel, V., Bethmann, J., Vollmer, M., Engeli, S., & Tzvetkov, M. V.
- Affiliations
- Universitätsmedizin Greifswald (DE)
- Department of General Pharmacology, Institute of Pharmacology University Medicine Greifswald Greifswald Germany
- Corresponding author
- Tzvetkov, Mladen V.
- ORCID
- Venue
- Clinical Pharmacology & Therapeutics
- Publisher
- Wiley
- Published
- 2024-11-03
- Volume
- 117
- Issue
- 1
- Pages
- 250-260
- ISSN
- 0009-9236 (ISSN-L)
- 1532-6535
- PMC
- PMC11652804
- OpenAlex
- W4404012159
- Cited by
- 16
- References
- 50
- Citations by year
- 2026: 12 · 2025: 4
- FWCI
- 6.71
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Clinical Pharmacology & Therapeutics (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Pharmacology › Berberine and alkaloids research
- Keywords
- berberine, CYP2D6, OCT1, pharmacokinetics, sex differences, drug metabolism, transporter polymorphisms, poor metabolizers, oral bioavailability, drug-drug interactions
- MeSH terms
- Adult, Animals, Berberine, Biological Availability, Female, Genotype, Humans, Male, Polymorphism, Genetic, Sex Factors, Mice, Knockout, Cytochrome P-450 CYP2D6, Octamer Transcription Factor-1, Mice, Young Adult
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