The effects of St John's wort (Hypericum perforatum) on human cytochrome P450 activity

Background St John's wort (Hypericum perforatum) is a popular over-the-coun ter dietary supplement and herbal remedy that has been implicated in drug i nteractions with substrates of several cytochrome P450 (CYP) isozymes. The effect of St John's wort on CYP activity in vivo was examined with a probe drug cocktail. Methods: Twelve healthy subjects (5 female, 7 male) completed this 3-period , open-label, fixed schedule study. Tolbutamide (CYP2C9), caffeine (CYP1A2) , dextromethorphan (CYP2D6), oral midazolam (intestinal wall and hepatic CY P3A), and intravenous midazolam (hepatic CYP3A) were administered before, w ith short-term St John's wort dosing (900 mg), and after 2 weeks of intake (300 ing 3 times a day) to determine CYP activities. Results. Short-term administration of St John's wort had no effect on CYP a ctivities. Long-term St John's wort administration caused a significant (P < .05) increase in oral clearance of midazolam from 121.8 +/- 70.7 to 254.5 +/- 127.8 and a corresponding significant decline in oral bioavailability from 0.28 +/- 0.15 to 0.17 +/- 0.06. In contrast to the > 50% decrease in t he area under the plasma concentration-time curve (AUC) when midazolam was administered orally, long-term St John's wort administration caused a 20% d ecrease in AUC when midazolam was given intravenously. There was no change in CYP1A2, CYP2C9, or CYP2D6 activities as a result of St John's wort admin istration. Conclusion: Long-term St John's wort administration resulted in a significa nt and selective induction of CYP3A activity in the intestinal wall. St Joh n's wort did not alter the CYP2C9, CYP1A2, or CYP2D6 activities. Reduced th erapeutic efficacy of drugs metabolized by CYP3A should be anticipated duri ng longterm administration of St John's wort.