Journal article
Mechanism of Altered Metformin Distribution in Nonalcoholic Steatohepatitis
Diabetes (New York, N.Y.), Vol.64(9), pp.3305-3313
09/2015
Handle:
https://hdl.handle.net/2376/100355
PMCID: PMC4542448
PMID: 26016715
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.
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Details
- Title
- Mechanism of Altered Metformin Distribution in Nonalcoholic Steatohepatitis
- Creators
- John D Clarke - Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZAnika L Dzierlenga - Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZNicholas R Nelson - Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZHui Li - Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZSamantha Werts - Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZMichael J Goedken - Translational Sciences, Research Pathology Services, Rutgers University, New Brunswick, NJNathan J Cherrington - Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ cherrington@pharmacy.arizona.edu
- Publication Details
- Diabetes (New York, N.Y.), Vol.64(9), pp.3305-3313
- Academic Unit
- Pharmaceutical Sciences, Department of
- Publisher
- United States
- Grant note
- HD062489 / NICHD NIH HHS R01 AI083927 / NIAID NIH HHS T32 ES007091 / NIEHS NIH HHS ES007091 / NIEHS NIH HHS R01 HD062489 / NICHD NIH HHS AI083927 / NIAID NIH HHS P30 ES006694 / NIEHS NIH HHS R01 ES019487 / NIEHS NIH HHS ES019487 / NIEHS NIH HHS
- Identifiers
- 99900546619801842
- Language
- English
- Resource Type
- Journal article