Effects of resveratrol on P-glycoprotein and cytochrome P450 3A in vitro and on pharmacokinetics of oral saquinavir in rats

Background: The intestinal cytochrome P450 3A (CYP 3A) and P-glycoprotein (P-gp) present a barrier to the oral absorption of saquinavir (SQV). Resveratrol (RESV) has been indicated to have modulatory effects on P-gp and CYP 3A. Therefore, this study was to investigate the effects of RESV on P-gp and CYP 3A activities in vitro and in vivo on oral SQV pharmacokinetics in rats. Methods: In vitro, intestinal microsomes were used to evaluate RESV effect on CYP 3A-mediated metabolism of SQV; MDR1-expressing Madin-Darby canine kidney (MDCKIIMDR1) cells were employed to assess the impact of RESV on P-gp-mediated efflux of SQV. In vivo effects were studied using 10 rats randomly assigned to receive oral SQV (30 mg/kg) with or without RESV (20 mg/kg). Serial blood samples were obtained over the following 24 h. Concentrations of SQV in samples were ascertained using high-performance liquid chromatography-tandem mass spectrometry analysis. Results: RESV (1-100 mu M) enhanced residual SQV (% of control) in a dose-dependent manner after incubation with intestinal microsomes. RESV (1-100 mu M) reduced the accumulation of SQV in MDCKII-MDRI cells in a concentration-dependent manner. A double peaking phenomenon was observed in the plasma SQV profiles in rats. The first peak of plasma SQV concentration was increased, but the second peak was reduced by coadm in istration with RES V. The mean AUC(0-infinity) of SQV was slightly decreased, with no statistical significance probably due to the high individual variation. Conclusion: RESV can alter the plasma SQV concentration profiles, shorten the T-max of SQV. RESV might also cause a slight decrease tendency in the SQV bioavailability in rats.