title: Effects of St. John's wort extract on indinavir pharmacokinetics in rats: differentiation of intestinal and hepatic impacts.
abstract: OBJECTIVE
  To evaluate the possible herb-drug interaction of St. John's wort (SJW) extracts with indinavir in rats and to set up a model for characterizing pre-systemic sites for the interactions between orally administered herbs and pharmaceuticals.
  
  
  METHODS
  The in vivo pharmacokinetic study and in situ single-pass intestinal perfusion model were employed in the research. Plasma indinavir concentration and cytochrome P450 3A activities were measured by high-pressure liquid chromatography and spectrophotometric assays, respectively.
  
  
  RESULTS
  Oral administration of either 150 or 300 mg/day SJW for 15 days significantly reduced indinavir plasma levels with certain pharmacokinetic parameter changes. The cytochrome P450 3A analysis suggested that this interaction was attributable to the induction of indinavir metabolism. Further perfusion study demonstrated that both small intestine and the liver contributed significantly to the reduction of indinavir bioavailability and was flow rate-dependent. Moreover, the small intestine was the major site for the pre-systemic metabolism of indinavir, whether with or without SJW pretreatment.
  
  
  CONCLUSIONS
  Herb-drug pharmacokinetic interactions between SJW and indinavir can be clearly observed in the Wistar rat model. Particularly, the respective first-pass effect contributed by the small intestine and the liver could be differentiated and quantified. The application of the animal model to investigating herb-drug interactions or other relevant research purposes is envisioned.
authors: School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan. yfho@ntu.edu.tw
authors: Yunn-Fang
authors: YF
authors: Ho
authors: Da-Kong
authors: DK
authors: Huang
authors: Wei-Cherng
authors: WC
authors: Hsueh
authors: Ming-Yen
authors: MY
authors: Lai
authors: Hsiu-Ying
authors: HY
authors: Yu
authors: Tung-Hu
authors: TH
authors: Tsai
mesh_terms: D000818:Animals; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D017320:HIV Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D041743:Herb-Drug Interactions; D020902:Hypericum / Q000737:chemistry*; D019469:Indinavir / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010936:Plant Extracts / Q000009:adverse effects* / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D017320:HIV Protease Inhibitors; D010936:Plant Extracts; D019469:Indinavir; D051544:Cytochrome P-450 CYP3A