Effects of St. John's wort extract on indinavir pharmacokinetics in rats: differentiation of intestinal and hepatic impacts.
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.
Ho
Yunn-Fang
YF
School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan. yfho@ntu.edu.tw
Huang
Da-Kong
DK
Hsueh
Wei-Cherng
WC
Lai
Ming-Yen
MY
Yu
Hsiu-Ying
HY
Tsai
Tung-Hu
TH
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
D017320:HIV Protease Inhibitors; D010936:Plant Extracts; D019469:Indinavir; D051544:Cytochrome P-450 CYP3A