Pharmacokinetics and Drug Disposition
Clinical Pharmacology & Therapeutics (2004) 76, 428–440; doi: 10.1016/j.clpt.2004.07.007
In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes: Citrus aurantium, Echinacea purpurea, milk thistle, and saw palmetto*
Bill J. Gurley PhD1, Stephanie F. Gardner PharmD, EdD1, Martha A. Hubbard MS1, D. Keith Williams PhD1, W. Brooks Gentry MD1, Julie Carrier PhD1, Ikhlas A. Khan PhD1, David J. Edwards PharmD1 and Amit Shah1
1Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, College of Pharmacy, Little Rock; Department of Pharmacy Practice, University of Arkansas for Medical Sciences, College of Pharmacy, Little Rock; Department of Biometry, University of Arkansas for Medical Sciences, College of Medicine, Little Rock; Department of Anesthesiology, University of Arkansas for Medical Sciences, College of Medicine, Little Rock; Department of Biological and Agricultural Engineering, University of Arkansas, Fayetteville; National Center for Natural Products Research, University of Mississippi, School of Pharmacy, University; Department of Pharmaceutics, University of Mississippi, School of Pharmacy, University; Department of Pharmacy Practice, Wayne State University, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit
Correspondence: Bill J. Gurley, PhD, University of Arkansas for Medical Sciences, College of Pharmacy, Departments of Pharmaceutical Sciences and Pharmacy Practice, 4301 W Markham St, Slot 522, Little Rock, AR 72205
*Supported through a grant from the Gustavus and Louise Pfeiffer Research Foundation.
Received 26 May 2004; Accepted 9 July 2004.
Abstract
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.
