title: Mechanism of Altered Metformin Distribution in Nonalcoholic Steatohepatitis.
abstract: Metformin is an antihyperglycemic 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/6J (wild type [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 with 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.
authors.affiliation: Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ.
authors.forename: John D
authors.initials: JD
authors.lastname: Clarke
authors.affiliation: Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ.
authors.forename: Anika L
authors.initials: AL
authors.lastname: Dzierlenga
authors.affiliation: Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Nelson
authors.affiliation: Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ.
authors.forename: Samantha
authors.initials: S
authors.lastname: Werts
authors.affiliation: Translational Sciences, Research Pathology Services, Rutgers University, New Brunswick, NJ.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Goedken
authors.affiliation: Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ cherrington@pharmacy.arizona.edu.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Cherrington
mesh_terms: D000818:Animals; D002794:Choline; D003924:Diabetes Mellitus, Type 2; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008687:Metformin / Q000378:metabolism / Q000493:pharmacokinetics*; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism* / Q000473:pathology; D050811:Octamer Transcription Factor-1 / Q000235:genetics / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D012333:RNA, Messenger / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D007004:Hypoglycemic Agents; C514424:MATE1 protein, mouse; D050811:Octamer Transcription Factor-1; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C494166:Pou2f1 protein, mouse; D012333:RNA, Messenger; C491012:Slc22a2 protein, mouse; D008687:Metformin; D008715:Methionine; D002794:Choline