Organic cation transporter and multidrug and toxin extrusion 1 co-mediated interaction between metformin and berberine

• Published in: European journal of pharmaceutical sciences 2019-01, Vol.127, p.282-290
• Main Authors: Shi, Rong, Xu, Zhangyao, Xu, Xining, Jin, Jingyi, Zhao, Yining, Wang, Tianming, Li, Yuanyuan, Ma, Yueming
• Format: Article
• Language: English
• Subjects: Adipose Tissue - metabolism; Animals; Antiporters - genetics; Antiporters - metabolism; Berberine; Berberine - blood; Berberine - pharmacokinetics; Catecholamine Plasma Membrane Transport Proteins - genetics; Catecholamine Plasma Membrane Transport Proteins - metabolism; Dogs; Drug Interactions; Female; Hypoglycemic Agents - blood; Hypoglycemic Agents - pharmacokinetics; Intestinal Mucosa - metabolism; Kidney - metabolism; Liver - metabolism; Madin Darby Canine Kidney Cells; Male; Metformin; Metformin - blood; Metformin - pharmacokinetics; Multidrug and toxin extrusion; Muscle, Skeletal - metabolism; Organic Cation Transport Proteins - genetics; Organic Cation Transport Proteins - metabolism; Organic cation transporter; Organic Cation Transporter 2 - genetics; Organic Cation Transporter 2 - metabolism; Pharmacokinetic interaction; Rats, Sprague-Dawley
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2018.11.010

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 (Cmax), area under the curve from 0 to 4 h (AUC0–4h), 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 (IC50) values of 18.8, 1.02, and 10.7 μM, respectively. In contrast, co-administration of metformin increased the Cmax and AUC0-4h 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. [Display omitted]