In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes: Citrus aurantium, Echinacea purpurea, milk thistle, and saw palmetto

Objectives Phytochemical‐mediated modulation of cytochrome P450 (CYP) activity may underlie many herb‐drug interactions. Single‐time point phenotypic metabolic ratios were used to determine whether long‐term supplementation of Citrus aurantium, Echinacea purpurea, milk thistle (Silybum marianum), or saw palmetto (Serenoa repens) extracts affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activity. Methods Twelve healthy volunteers (6 women, 6 men) were randomly assigned to receive C aurantium, E purpurea, milk thistle, or saw palmetto 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 debrisoquin (INN, debrisoquine), were administered before (baseline) and at the end of supplementation. Presupplementation and postsupplementation phenotypic trait measurements were determined for CYP3A4, CYP1A2, CYP2E1, and CYP2D6 by use of 1‐hydroxymidazolam/midazolam serum ratios (1‐hour sample), paraxanthine/caffeine serum ratios (6‐hour sample), 6‐hydroxychlorzoxazone/chlorzoxazone serum ratios (2‐hour sample), and debrisoquin urinary recovery ratios (8‐hour collection), respectively. The content of purported “active” phytochemicals was determined for each supplement. Results Comparisons of presupplementation and postsupplementation phenotypic ratios suggested that these particular supplements had no significant effect on CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activity. Phytochemical profiles indicated that C aurantium was devoid of the CYP3A4 inhibitor 6′,7′‐dihydroxybergamottin. Quantities of fatty acids, flavonolignans, and cichoric acid were consistent with label claims for saw palmetto, milk thistle, and E purpurea, respectively. Conclusions Botanical supplements containing C aurantium, milk thistle, or saw palmetto extracts appear to pose a minimal risk for CYP‐mediated herb‐drug interactions in humans. Although the effects of E purpurea on CYP activity were minor, further study into the interaction potential of this botanical is merited. Clinical Pharmacology & Therapeutics (2004) 76, 428–440; doi: 10.1016/j.clpt.2004.07.007