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NASH-Linked Changes Impact Metformin Pharmacokinetics

Mice study shows alteration in kidney transporter expression, altered metformin pharmacokinetics

THURSDAY, June 4, 2015 (HealthDay News) — Nonalcoholic steatohepatitis (NASH)-associated changes in liver function affect kidney transporter expression and metformin pharmacokinetics, according to an experimental study published online May 27 in Diabetes Care.

John D. Clarke, Ph.D., from the University of Arizona in Tucson, and colleagues examined how NASH affects kidney transporter expression and metformin pharmacokinetics. They administered a single oral dose of [14C] metformin to C57BL/6 (WT) mice and mice with diabetes (ob/ob). Mice were fed a methionine and choline deficient (MCD) diet or a control diet.

The researchers found that, compared with WT/Control mice, metformin plasma concentrations were slightly elevated in the WT/MCD and ob/Control groups, and 4.8-fold higher in ob/MCD mice. In both genotypes, the MCD diet significantly increased plasma half-life and mean residence time, and decreased oral clearance. These changes were attributable to ob/ob and MCD diet-specific reductions in the kidney mRNA expression of Oct2 and Mate1; Oct1 mRNA expression was reduced only 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,” the authors write.

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