(Verbatim from the application): The herbal medicine St. John's Wort, sold over the counter in the United States, has attracted tremendous lay and scientific attention for its potential use in the treatment of depression. Indeed, NIMH is sponsoring the first multi-center trial in this country evaluating the efficacy of St. John's wort for the treatment of depression. While much work has investigated the mechanism of action and therapeutic potential of St. John's wort, the potential for drug interactions between this herbal medicine and other medicines, including anti-depressants, has been largely ignored. There is evidence to suggest that St. John's wort induces the cytochrome P450 (CYP) enzyme system including CYP3A enzymes, which are the most abundant CYP enzymes in both the intestine and liver. A major determinant of the circulating concentrations of CYP-metabolized drugs is the activity of CYP enzymes. That St. John's wort may induce the metabolism of co-administered drugs would be of particular importance in depressed patients who may receive multiple drugs including anti-depressants, which are primarily metabolized by CYP enzymes. Induction of CYP enzymes would lead to decreased concentrations of co-administered drugs and increased concentrations of metabolites, each of which may affect efficacy and/or toxicity. The first specific aim is to assess effects of St John's wort on CYP3A metabolism by administering midazolam to subjects in randomized parallel groups before and after receiving either placebo- or St. John's Wort at two doses (300 and 600 tid for two weeks). Pharmacokinetics and pharmacodynamic measures (saccadic eye movements) of midazolam will be performed. The second specific aim is to study the effects of St. John's Wort on other CYP pathways, specifically CYP1A2 using caffeine as a probe, CYP2C9 using flurbiprofen as a probe, and CYP2C19 using mephenytoin as a """"""""cocktail"""""""" probe approach on the day following the midazolam studies.
In specific aim 3, the investigator proposes to validate a new method for characterizing both hepatic and intestinal in vivo CYP3A activity using semisimultaneous i.v. and oral midazolam administration (oral midazolam followed by i.v. at 6 hr after oral dosing) and comparing this to separate day administration of i.v. and oral midazolam (Specific Aim 3).
