INFLUENCE OF ATORVASTATIN ON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF PIOGLITAZONE IN DIABETIC RATS
Atorvastatin is a selective 3- hydroxyl-3- methylglutarayl-coenzyme A (HMG-CoA) reductase competitive inhibitor, used for the treatment of hyperlipidaemia. It is metabolized by CYP 3A4 and 3A5 [Cytochorme P450 (system)] isoenzymes in liver. It also has moderate inhibitory action on metabolizing enzymes like CYP 3A4, 2C9 and 2D6. Hence there is more possibility of Atorvastatin for inhibition of metabolism of Pioglitazone, by both CYP2C isozyme and 3A4. We have studied the effects of atorvastatin on the pharmacokinetics (PK) and pharmacodynamics (PD) of Pioglitazone in experimental diabetic rats. Atorvastatin (20 mg/kg p.o.) was given to Streptozotocin (STZ) induced diabetic rats for 7 consecutive days followed by Pioglitazone (10 mg/kg p.o.). In the rats co-treated with Atorvastatin and Pioglitazone, fasting plasma glucose concentration was further reduced, markedly as compared with Pioglitazone-treated animals. In co-treated group, the pharmacokinetic parameters like clearance of Pioglitazone was reduced, while area under the plasma concentration time curve, peak plasma concentration and elimination half-life were significantly increased when compared to Pioglitazone alone administered rats. The results of this study shown that atorvastatin led to the PK/PD changes have been due to Pioglitazone increased bioavailability, decreased volume of distribution, and/or decreased total clearance may be due to the inhibition of Cytochrome P450 metobolic system.