Abstract
The aim of this study was to report the effect of diabetes mellitus on pharmacokinetics of verapamil in route-dependent manner. Diabetic rats were induced by streptozotocin. Plasma concentration of verapamil and its metabolite, norverapamil, were measured following oral (10 mg/kg) or intravenous (1 mg/kg) administration. The concentrations of verapamil in portal plasma after oral administration were also determined. Norverapamil formation was used for assessing CYP3A activity in hepatic and intestinal microsomes of diabetic rats. The protein level of CYP3A1 and CYP3A2 in liver and intestine were measured using western blot. It was found that the diabetes significantly increased plasma concentration of verapamil and norverapmil after oral administration, which resulted in a 74% increase in the AUC of verapamil, but the ratio of AUC(norverapamil)/AUC(verapamil) was significantly decreased by 38%. In contrast, diabetes significantly decreased the AUC of verapamil by 22% following intravenous administration. Diabetes also resulted in increased AUC of verapamil in portal vein by 3.8-fold compared with normal rats. The absolute bioavailability of verapamil was higher than that of normal rats. In vitro study showed that increased CYP3A activity in the hepatic microsome and decreased CYP3A activity in the intestinal microsome were accompanied by the increase and decrease of the protein expression of CYP3A1/2 in liver and intestine of diabetic rats, respectively. In conclusion, diabetes mellitus revealed a tissue specific effect on CYP3A activity and expression (induced in liver and inhibited in intestine), resulting in the opposite pharmacokinetic behaviors of verapamil following oral and intravenous administration to diabetic rats.
- Received July 27, 2010.
- Accepted December 6, 2010.
- The American Society for Pharmacology and Experimental Therapeutics