Background: St John's wort (Hypericum perforatum) is a popular over-the-counter dietary supplement and herbal remedy that has been implicated in drug interactions 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 CYP3A), and intravenous midazolam (hepatic CYP3A) were administered before, with short-term St John's wort dosing (900 mg), and after 2 weeks of intake (300 mg 3 times a day) to determine CYP activities.
Results: Short-term administration of St John's wort had no effect on CYP activities. 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 the area under the plasma concentration-time curve (AUC) when midazolam was administered orally, long-term St John's wort administration caused a 20% decrease 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 administration.
Conclusion: Long-term St John's wort administration resulted in a significant and selective induction of CYP3A activity in the intestinal wall. St John's wort did not alter the CYP2C9, CYP1A2, or CYP2D6 activities. Reduced therapeutic efficacy of drugs metabolized by CYP3A should be anticipated during long-term administration of St John's wort.