Changes in metformin pharmacokinetics after intravenous and oral administration to rats with short-term and long-term diabetes induced by streptozotocin

It has been reported that metformin was primarily metabolized via hepatic CYP2C11, 2D1, and 3A1/2 in rats, and the expression and mRNA levels of hepatic CYP2C11 and 3A1 decreased and increased, respectively, whereas the expression of CYP2D1 was not changed in rat model of diabetes induced by streptozotocin (DMIS). Also minimizing the toxic effects of streptozotocin by carrying out experiments 4-5 weeks after streptozotocin injection has been reported. Thus, the pharmacokinetics of metformin was evaluated in rat model of DMIS at the 7th and the 29th days after streptozotocin injection. After intravenous administration of metformin (100 mg/kg) to rat model of DMIS, the CL_R became significantly faster (46.9% and 77.8% increase for the 7th and the 29th days, respectively; due to urine flow rate-dependent timed-interval renal clearance of the drug) and CL_NR became significantly slower (28.0% and 34.3% decrease, respectively; due to decreased hepatic CYP2C11) than in their respective controls. After oral administration of metformin (100 mg/kg) to rat model of DMIS, the AUC became significantly smaller (18.6% and 33.7% decrease for the 7th and the 29th days, respectively) than in their respective controls. The CL_NR of metformin were comparable between two rat models of DMIS.