흰쥐에서 프라바스타틴과 와파린의 약물동태학적 상호작용

Abstract

The aim of this study was to investigate the effect of pravastatin on the pharmacokinetics of warfarin after oral and intravenous administration of warfarin in rats. Warfarin was administered orally (0.2 mg/kg) or intravenously (0.05 mg/kg) without or with oral administration of pravastatin (0.1 or 0.4 mg/kg) in rats. The effect of pravastatin on the P-glycoprotein (P-gp) as well as cytochrome P450 (CYP) 3A4 activity was also evaluated. Pravastatin inhibited CYP3A4 enzyme activity with 50 % inhibition concentration (IC50) of 9.1 ?. Compared to those animals in the oral control group (warfarin without pravastatin), the area under the plasma concentration?ime curve (AUC) of warfarin was significantly greater (0.1 mg/kg, P<0.05; 0.4 mg/kg, P<0.01) by 26.5?3.5 %, and the peak plasma concentration (Cmax) was significantly higher (0.4 mg/kg, P<0.05) by 26.2 % after oral administration of warfarin with pravastatin, respectively. Consequently, the relative bioavailability of warfarin increased by 1.26- to 1.53-fold and the absolute bioavailability of warfarin with pravastatin was significantly greater by 61.7?2.5 % compared to that in the control group (47.4 %). In contrast, pravastatin had no effect on any pharmacokinetic parameters of warfarin given intravenously. Therefore, the enhanced oral bioavailability of warfarin may be due to inhibition of CYP 3A4-mediated metabolism in the intestine and/or liver rather than elimination, resulting in reducing first-pass metabolism by pravastatin.