In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes

Abstract

Objectives-Phytochemical-mediated modulation of cytochrome P-450 activity may underlie many herb-drug interactions. Single time-point, phenotypic metabolic ratios were used to determine whether long-term supplementation of goldenseal (Hydrastis canadensis), black cohosh (Cimicifuga racemosa), kava kava (Piper methysticum), or valerian (Valeriana officinalis) extracts affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4/5 activity.Methods-Twelve healthy volunteers (6 females) were randomly assigned to receive goldenseal, black cohosh, kava kava, or valerian for 28 days. For each subject, a 30-day washout period was interposed between each supplementation phase. Probe drug cocktails of midazolam and caffeine, followed 24 hours later by chlorzoxazone and debrisoquine were administered before (baseline) and at the end of supplementation. Pre-and post-supplementation phenotypic trait measurements were determined for CYP3A4/5, CYP1A2, CYP2E1, and CYP2D6 using 1-hydroxymidazolam/ midazolam serum ratios (1-hour sample), paraxanthine/caffeine serum ratios (6-hour sample), 6-hydroxychlorzoxazone/chlorzoxazone serum ratios (2-hour sample), and debrisoquine urinary recovery ratios (8-hour collection), respectively. The content of purported "active" phytochemicals was determined for each supplement. Conclusions-Botanical supplements containing goldenseal strongly inhibited CYP2D6 and CYP3A4/5 activity in vivo, while kava inhibited CYP2E1 and black cohosh weakly inhibited CYP2D6. Accordingly, serious adverse interactions may result from the concomitant ingestion of goldenseal supplements and drugs that are CYP2D6 and CYP3A4/5 substrates. Kava kava and black cohosh may interact with CYP2E1 and CYP2D6 substrates, respectively. Valerian appears less likely to produce CYP-mediated herb-drug interactions.

The Interaction of Selected Phytochemicals, HIV Drugs, and Commercial-Source Herbal Teas and Capsules with Human Cytochrome P450 3A4 and P-glycoprotein

“…As examples, some recent clinical studies (Piscitelli et al, 2002a,b;Gurley et al, 2004Gurley et al, , 2005 found that specific preparations of some NHPs used in this study (e.g., milk thistle and goldenseal), known to contain constituents that are P-gp substrates and capable of inhibiting CYP3A4 (and/or other CYP isoforms) metabolism in vitro, had little impact on the overall metabolism of many concomitantly administered drugs (including some HIV protease inhibitors). Although the extrapolation of the current in vitro findings and those from the concurrent study to clinical effects may well be considered speculative, the overall in vitro data should still be considered as a signal of potential in vivo interactions.…”

In vitro inhibition of cytochrome P-450 activities and quantification of constituents in a selection of commercial Rhodiola rosea products

“…Grapefruit juice is a particularly well-known inhibiting agent towards numerous CYP enzymes, both in vitro and in vivo, with clinically relevant changes in metabolism of conventional medicines (Hanley et al 2011). Kava and Ginkgo biloba have also shown effects in vivo, with significant changes in drug metabolism and clinical effects in humans (Gurley et al 2002(Gurley et al , 2005Abad et al 2010). …”

Valerian: No evidence for Clinically Relevant interactions

“…However, critical assessment of these studies suggests that the clinical relevance of the findings is questionable due to various methodological limitations (Table 1). This is underlined by the available clinical interaction studies on CYP isoenzymes, which do not indicate a relevant drug interaction potential of valerian in healthy volunteers [35,37].…”

“…One of these publications [34] contains, in addition, data on animal studies. Two publications [35,37] present clinical studies on pharmacokinetic interactions. 8 studies are available on the subject of pharmacodynamic interactions, thereof two in vitro and three animal studies, one clinical study, and in addition two case reports.…”

“…In another study, twelve healthy volunteers (six men and six women, age mean ± SD = 24 ± 3 years, weight 69.3 ± 14.2 kg KGW) were randomly assigned to receive valerian (DER 4 : 1, no standardization claim) for 28 days, three times daily 125 mg [35]. Before and after the test period, the activities of CYP 3A4/5 (1-hydroxymidazolam/midazolam serum ratio), CYP 1A2 (paraxanthine/caffeine serum ratio), CYP 2E1 (hydroxychlorzoxazone/chlorzoxazone serum ratio), and CYP 2D6 (debrisoquine urinary recovery ratio) were determined.…”