Influence of atorvastatin on the pharmacokinetics and pharmacodynamics of glyburide in normal and diabetic rats

Abstract

Atorvastatin is a selective HMG-CoA reductase competitive inhibitor, used for the treatment of hyperlipidaemia. It is metabolized by CYP 3A4 and 3A5 isoenzymes in liver. It also has moderate inhibition on metabolizing enzymes like CYP 2C9, 2D6 and 3A4. Hence there is more possibility of atorvastatin for inhibition of metabolism of glyburide, by both CYP 2C9 and 3A4. We have studied the effects of atorvastatin on the pharmacodynamics and pharmacokinetics of glyburide in experimental diabetic rats. Atorvastatin (20mg/kg p.o.) was given to alloxan-induced diabetic rats for 7 consecutive days followed by glyburide (10mg/kg p.o.). In the rats co-treated with atorvastatin and glyburide, fasting plasma glucose concentration (60.69±5.70%) was further reduced, markedly as compared with glyburide-treated animals. In co-treated group, the pharmacokinetic parameters like clearance (27.83±3.55l/h) of glyburide was reduced, while peak plasma concentration (18.39±5.29μg/ml), area under the plasma concentration time curve (120.02±15.17μg/ml/h) and elimination half-life (4.09±0.50h) were significantly increased when compared to glyburide alone administered rats. The results of this study revealed that atorvastatin led to the PK/PD changes have been due to glyburide increased bioavailability, decrease volume of distribution, and/or decrease total clearance may be due to the inhibition of cytochrome P450 metobolic system.