John D. Clarke, Anika L. Dzierlenga, Nicholas R. Nelson, Hui Li, Samantha Werts, Michael J. Goedken, Nathan J. Cherrington

Metformin is an anti-hyperglycemic drug that is widely prescribed for type-2 diabetes mellitus and is currently being investigated for the treatment of nonalcoholic steatohepatitis (NASH). NASH is known to alter hepatic membrane transporter expression and drug disposition similarly in humans and rodent models of NASH. Metformin is almost exclusively eliminated through the kidney primarily through active secretion mediated by Oct1, Oct2, and Mate1. The purpose of this study was to determine how NASH affects kidney transporter expression and metformin pharmacokinetics. A single oral dose of [(14)C] metformin was administered to C57BL/6 (WT) and diabetic ob/ob mice fed either a control diet or a methionine and choline deficient (MCD) diet. Metformin plasma concentrations were slightly increased in the WT/MCD and ob/Control groups, whereas plasma concentrations were 4.8-fold higher in ob/MCD mice compared to WT/Control. The MCD diet significantly increased plasma half-life and mean residence time and correspondingly decreased oral clearance in both genotypes. These changes in disposition were caused by ob/ob- and MCD diet-specific decreases in the kidney mRNA expression of Oct2 and Mate1, whereas Oct1 mRNA expression was only decreased in ob/MCD mice. These results indicate that the diabetic ob/ob genotype and the MCD disease model alter kidney transporter expression and alter the pharmacokinetics of metformin, potentially increasing the risk of drug toxicity.