Pharmacokinetics of diclofenac in rat model of diabetes mellitus induced by alloxan or steptozotocin

Abstract

The pharmacokinetics of diclofenac were compared after intravenous and oral administration at a dose of 5 mg/kg in a rat model of diabetes mellitus induced by alloxan (DMIA) or streptozotocin (DMIS), and their respective control rats. Diclofenac was reported to be metabolized via the hepatic microsomal cytochrome P450 (CYP) 2C11 in male rats. The expression and mRNA level of CYP2C11 decreased in rat models of DMIA and DMIS. Hence, the time-averaged nonrenal clearance (Clnr) of diclofenac was expected to be slower in a rat model of diabetes. As expected, after intravenous administration, the Clnr values of diclofenac were significantly slower in rat models of DMIA (11.3 versus 13.6 ml/min/kg) and DMIS (8.06 versus 15.2 ml/min/kg) than those in control rats. As a result, the total area under the plasma concentration-time curve from time zero to time infinity (AUC) values were significantly greater in rat models of DMIA (435 versus 367 microg min/ml) and DMIS (540 versus 329 microg min/ml). However, after oral administration, the AUC from time zero to the last measured time, 12 h, in plasma (AUC0-12 h) values were comparable between the rat models of DMIA and DMIS and their control rats, and this could be due to changes in the first-pass effect of diclofenac and was not due to a decrease in the absorption of diclofenac in the rat models of diabetes.