ABSTRACT:Valerian (Valeriana officinalis) is a popular dietary supplement. The objective of this study was to assess the influence of a valerian extract on the activity of the drug-metabolizing enzymes cytochrome P450 2D6 (CYP2D6) and 3A4. Probe drugs dextromethorphan (30 mg; CYP2D6 activity) and alprazolam (2 mg; CYP3A4 activity) were administered orally to healthy volunteers (n ؍ 12) at baseline and again after exposure to two 500-mg valerian tablets (1000 mg) nightly for 14 days. The valerian supplement contained a total valerenic acid content of 5.51 mg/tablet. Dextromethorphan to dextorphan metabolic ratios (DMRs) and alprazolam pharmacokinetics were determined at baseline and after valerian treatment. Valerian (Valeriana officinalis) extracts are marketed as dietary supplements in the United States and were among the top 10 bestselling herbal supplements in the United States in 2002 (Blumenthal, 2003). Although they are currently promoted as a sedative/hypnotic, clinical trials are presently inconclusive with regard to the efficacy for insomnia (Houghton, 1999;Stevinson and Ernst, 2000;Krystal and Ressler, 2001).Valerian supplements contain a complex mixture of chemical constituents (Shohet et al., 2001). The main constituents are valerenic acid and its derivatives contained in the volatile oil (Houghton, 1999). These main constituents are widely thought to contribute to the putative sedative effects, although clinical effects may be a result of synergistic activity from numerous constituents. The valepotriates have also been investigated for pharmacologic activity but are relatively unstable and are often not present in most commercial supplements (Bos et al., 2002). Minor constituents include various alkaloids, furanofuran lignans, and free amino acids (Houghton, 1999). Valerian is well recognized by its unpleasant odor that is attributed to isovaleric acid formation during processing and storage.The widespread use of valerian supplements suggests that use with conventional medications is inevitable, and the potential for drug interactions is undefined (Fugh-Berman and Ernst, 2001;Markowitz et al., 2003b;Huang et al., 2004). The present study was undertaken in healthy volunteers to determine whether a valerian supplement containing known quantities of valerenic acid and its derivatives could alter the activity of two major drug-metabolizing enzymes, cytochrome P450 2D6 (CYP2D6) and CYP3A4 in healthy volunteers. These two enzymes were chosen since, together, they contribute to the metabolism of a substantial number of both prescription and nonprescription medications (Wrighton and Thummel, 2000;Zanger and Eichelbaum, 2000;Burk and Wojnowski, 2004). To our knowledge, this is the first clinical study assessing whether a standardized valerian supplement may participate in drug interactions mediated by any of the P450 enzymes.
Materials and MethodsSubjects. The study was approved by the Medical University of South Carolina's Office of Research Integrity, and subjects provided written informed consent before...