Effects of water deprivation on the pharmacokinetics of metformin in rats

It was reported that metformin was mainly metabolized via hepatic CYP2C11, 2D1 and 3A1/2 in rats, and in a rat model of dehydration, the expressions of hepatic CYP2C11 and 3A1/2 were not changed. Hence, it could be expected that the Cl_nr of metformin is comparable between two groups of rats if the contribution of CYP2D1 in the rat model of dehydration is not considerable. It was also reported that the timed-interval renal clearance of metformin was dependent on the urine flow rate in rats. In the rat model of dehydration, the 24 h urine output was significantly smaller than in the controls. Hence, the urinary excretion of metformin was expected to be smaller than the controls. The above expectations were proven as follows. After intravenous administration of metformin (100 mg/kg) to the rat model of dehydration, the Cl_nr were comparable between the two groups of rats. After both intravenous and oral administration of metformin (both 100 mg/kg) to the rat model of dehydration, the 24 h urinary excretion of the drug was significantly smaller than in the controls. After oral administration of metformin to the rat model of dehydration, the AUC was significantly greater (99.2% increase) than the controls.