Blöcher Jonas A, Meyer-Tönnies Marleen J, Morof Felix, Rönnpagel Vincent, Bethmann Jonas, Vollmer Marcus, Engeli Stefan, Tzvetkov Mladen V
Department of Clinical Pharmacology, Institute of Pharmacology, University Medicine Greifswald, Greifswald, Germany.
Department of General Pharmacology, Institute of Pharmacology, University Medicine Greifswald, Greifswald, Germany.
Clin Pharmacol Ther. 2025 Jan;117(1):250-260. doi: 10.1002/cpt.3454. Epub 2024 Nov 3.
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 of 7.0 μM, CL 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 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).
一种非处方产品黄连素（白毛茛中的主要生物碱）是摄取转运体OCT1和代谢酶CYP2D6的底物。这两个基因存在常见的功能多态性。约9%的欧洲人和美国白人是CYP2D6代谢不良者或OCT1转运不良者。在本研究中，我们调查了OCT1和CYP2D6多态性对黄连素在人体药代动力学的影响。我们在体外证实黄连素是OCT1的底物（K为7.0 μM，CL为306±29 μL/min/mg）。常见的OCT1等位基因3至6显示摄取减少至少65%，Oct1/2基因敲除小鼠在肝脏灌注实验中AUC高3.2倍。然而，在人体中，与参照参与者相比，OCT1转运不良者在黄连素药代动力学方面未显示任何差异。相反，CYP2D6多态性显著影响黄连素代谢，但仅在女性中如此。CYP2D6代谢不良的女性M1与黄连素的比值低80%。一般线性模型分析表明女性性别与CYP2D6基因型之间存在强烈的协同作用而非相加作用。总体而言，黄连素口服生物利用度低，但女性的AUC比男性高2.8倍，C比男性高3.6倍（P<0.001）。这些影响仅部分归因于性别与CYP2D6基因型的相互作用。总之，尽管黄连素是OCT1的底物，但OCT1缺乏并不影响人体中黄连素的药代动力学。相反，CYP2D6成为女性而非男性中黄连素代谢的关键酶，突出了性别特异性差异。我们认为，除CYP2D6代谢外的其他因素决定了黄连素的全身暴露，尤其是在男性中（NCT05463003）。
