The use of herbal agents by the lay public and medical professionals has accelerated in the last decade. Additionally, there has been increasing interest by the NIH National Center for Complementary & Alternative Medicine (NCCAM) and others in the safety and efficacy of herbal medicines in the treatment of a variety of medical and psychiatric conditions. It has also become evident that herbal medications are being used concomitantly with conventional prescription and over-the-counter medications. However, the systematic evaluation of the potential of these agents to interact with conventional medications has been generally neglected. Compounding this problem is the fact that even single entity herbal products can contain a multitude of naturally occurring chemicals which serve as candidates for potential herb-drug interactions by inhibiting or inducing specific hepatic isozymes. Numerous reports document the importance of pharmacokinetic interactions involving inhibition or induction of the cytochrome P450 (CYP) enzyme system. Importantly, recent publications have documented that clinically significant herb-drug interactions can occur. Prominent examples include herb-induced reductions in plasma concentrations of the anti-HIV medication indinavir and the immunosuppressant cyclosporine by St. John's wort (Hypericum perforatum). In vitro screening studies are of limited value due to difficulties in approximating physiologic concentrations, assessing the influence of non-hepatic metabolism, and accounting for the contribution of active metabolites. However, based upon findings of the effects of concurrently administered herbs on the metabolism of enzyme specific probe drug substrates alprazolam (CYP 3A4) and dextromethorphan (CYP 2D6), the potential specificity and magnitude of CYP enzyme inhibition and/or induction can be determined in normal volunteers. In a preliminary study in human subjects using this validated probe drug technique assessing inhibitory effects only, the investigators found no effects of St. John's wort on CYP 3A4 or CYP 2D6. In the present proposal, the 10 most commonly used herbal products in the US will be systematically evaluated for inhibition of CYP 3A4 and 2136, and induction of CYP 3A4. Collectively, these enzyme systems are involved in the metabolism of approximately 80% of all marketed medications. A combination of probe drugs will be given to normal volunteers both in the absence and presence of herbal medications. The plasma and urine concentration of these agents and their respective metabolites will be determined in order to evaluate individual herbal products degree and specificity of enzyme inhibitory or inductive effects. This data will fill a void regarding the relative safety of combining specific herbal agents with conventional medications and will serve as the basis for further investigations of other isozymes and herb interactions. Further, the proposed studies will complement existing and future NCCAM studies of agents such as St. John's wort and Gingko biloba.
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