Slower clearance of intravenous metformin in rats with acute renal failure induced by uranyl nitrate: Contribution of slower renal and non-renal clearances

It has been reported that metformin was primarily metabolized via hepatic CYP2C11, 2D1, and 3A1/2 in rats. It has also been reported that the protein expression and/or mRNA levels of hepatic CYP2C11, 2D subfamily, and 3A1 have decreased, decreased, and increased, respectively, in U-ARF rats. Thus, pharmacokinetic changes of intravenous metformin in U-ARF rats were evaluated. Metformin was administered intravenously at a dose of 50 mg/kg to control and U-ARF rats. After i.v. administration of metformin to U-ARF rats, its time-averaged total body clearance was significantly slower (95.2% decrease) than controls. This could have been due to both significantly slower time-averaged renal clearance (99.1% decrease; due to a urine flow rate-dependent timed-interval renal clearance of the drug, a decrease in renal OCT2, and/or an impaired kidney function in U-ARF rats) and time-averaged non-renal clearance (83.8% decrease; due to a decrease in hepatic CYP2C11 and 2D subfamily in U-ARF rats).