Department of Pharmacology, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Department of Pharmacology, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Eur J Pharm Sci. 2019 Jan 15;127:282-290. doi: 10.1016/j.ejps.2018.11.010. Epub 2018 Nov 11.
Metformin and berberine are often combined for treating diabetes. In the present study, we evaluated the drug-drug pharmacokinetic interaction between metformin and berberine after oral co-administration in vivo and the underlying mechanism. As revealed by comparison with the metformin-only group, berberine significantly decreased the maximum plasma concentration (C), area under the curve from 0 to 4 h (AUC), and urinary and bile excretion, and increased the kidney tissue concentration of metformin in rats. The non-everted intestinal sac study showed that berberine inhibited the absorption of metformin, and in transfected Madin-Darby canine kidney (MDCK)-rat organic cation transporter 1 (MDCK-rOCT1), MDCK-rat organic cation transporter 2 (MDCK-rOCT2), and MDCK-rat multidrug and toxin extrusion 1 (MDCK-rMATE1) cells, berberine significantly inhibited metformin transport mediated by OCT1, OCT2, and MATE1 in a concentration-dependent manner with half-maximal inhibitory concentration (IC) values of 18.8, 1.02, and 10.7 μM, respectively. In contrast, co-administration of metformin increased the C and AUC of berberine with no significant difference in pharmacokinetics parameters between co-administration and berberine-only groups. Furthermore, metformin increased kidney and liver concentrations and reduced the urinary and biliary excretion of berberine. Metformin (≥1 or ≥0.3 mM) decreased berberine transport in MDCK-rOCT1, MDCK-rOCT2, and MDCK-rMATE1 cells. However, metformin did not affect berberine concentration in MDCK-multidrug resistance protein 1 cells. These results suggest that the combination of metformin and berberine induced a pharmacokinetic interaction by cooperatively inhibiting OCT and MATE1-mediated transport.
二甲双胍和小檗碱常用于治疗糖尿病。在本研究中，我们评估了体内口服合用二甲双胍和小檗碱后的药物-药物药代动力学相互作用及其潜在机制。与单独使用二甲双胍相比，小檗碱显著降低了大鼠体内的最大血浆浓度（C）、0 至 4 小时的曲线下面积（AUC）、尿排泄和胆汁排泄，并增加了肾脏组织中二甲双胍的浓度。外翻肠囊研究表明，小檗碱抑制了二甲双胍的吸收，在转染的 MDCK-大鼠有机阳离子转运蛋白 1（MDCK-rOCT1）、MDCK-大鼠有机阳离子转运蛋白 2（MDCK-rOCT2）和 MDCK-大鼠多药和毒素外排蛋白 1（MDCK-rMATE1）细胞中，小檗碱以浓度依赖性方式显著抑制了 OCT1、OCT2 和 MATE1 介导的二甲双胍转运，其半最大抑制浓度（IC）值分别为 18.8、1.02 和 10.7 μM。相比之下，合用二甲双胍增加了小檗碱的 C 和 AUC，合用组与小檗碱单用组之间的药代动力学参数无显著差异。此外，二甲双胍增加了肾脏和肝脏浓度，减少了小檗碱的尿排泄和胆汁排泄。二甲双胍（≥1 或≥0.3 mM）降低了 MDCK-rOCT1、MDCK-rOCT2 和 MDCK-rMATE1 细胞中小檗碱的转运。然而，二甲双胍并不影响 MDCK-多药耐药蛋白 1 细胞中的小檗碱浓度。这些结果表明，二甲双胍和小檗碱的联合使用通过协同抑制 OCT 和 MATE1 介导的转运，引起了药代动力学相互作用。
