title: Effects of resveratrol on P-glycoprotein and cytochrome P450 3A in vitro and on pharmacokinetics of oral saquinavir in rats.
abstract: 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 (MDCKII-MDR1) 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 μM) enhanced residual SQV (% of control) in a dose-dependent manner after incubation with intestinal microsomes. RESV (1-100 μM) reduced the accumulation of SQV in MDCKII-MDR1 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 coadministration with RESV. The mean AUC0-∞of SQV was slightly decreased, with no statistical significance probably due to the high individual variation.
  
  
  CONCLUSIONS
  RESV can alter the plasma SQV concentration profiles, shorten the Tmaxof SQV. RESV might also cause a slight decrease tendency in the SQV bioavailability in rats.
authors.affiliation: Department of Pharmacy, Beijing Children's Hospital, Capital Medical University; Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China.
authors.forename: Jiapeng
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmacy, Beijing Children's Hospital, Capital Medical University; Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China.
authors.forename: Jingru
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, Beijing Children's Hospital, Capital Medical University; Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China.
authors.forename: Xiaotong
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Pharmacy, Beijing Children's Hospital, Capital Medical University.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Beijing Children's Hospital, Capital Medical University.
authors.forename: Libo
authors.initials: L
authors.lastname: Zhao
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004285:Dogs; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D007408:Intestinal Absorption; D008297:Male; D008861:Microsomes; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D019258:Saquinavir / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D013267:Stilbenes / Q000493:pharmacokinetics / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004791:Enzyme Inhibitors; D013267:Stilbenes; D051544:Cytochrome P-450 CYP3A; D019258:Saquinavir; D000077185:Resveratrol
keywords: CYP 3A; P-glycoprotein; pharmacokinetic; resveratrol; saquinavir