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First published on October 12, 2005; DOI: 10.1124/dmd.105.006312

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Received for publication July 13, 2005.
Revised October 6, 2005.
Accepted for publication October 7, 2005.

Effect of milk thistle (Silybum marianum) and black cohosh (Cimicifuga racemosa) supplementation on digoxin pharmacokinetics in humans

Bill Gurley 1*, Gary W Barone 2, D. Keith Williams 2, Julie Carrier 3, Philip Breen 1, C. Ryan Yates 4, Peng-fei Song 4, Martha A Hubbard 1, Yudong Tong 1, Sreekhar Cheboyina 5

1 University of Arkansas for Medical Sciences, College of Pharmacy 2 University of Arkansas for Medical Sciences, College of Medicine 3 University of Arkansas, College of Engineering 4 University of Tennessee Health Science Center 5 University of Mississippi, College of Pharmacy

* Address correspondence to: E-mail: gurleybillyj{at}uams.edu

Abstract

Phytochemical-mediated modulation of p-glycoprotein (P-gp) and other drug transporters may underlie many herb-drug interactions. Serial plasma concentration-time profiles of the P-gp substrate, digoxin, were used to determine whether supplementation with milk thistle or black cohosh modified P-gp activity in vivo. Sixteen healthy volunteers were randomly assigned to receive a standardized milk thistle (900 mg daily) or black cohosh (40 mg daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (600 mg daily, 7 days) and clarithromycin (1000 mg daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxicaps®, 0.4 mg) was administered orally before and at the end of each supplementation and control period. Serial digoxin plasma concentrations were obtained over 24 hours and analyzed by chemiluminescent immunoassay. Comparisons of AUC(0-3), AUC(0-24), Cmax,, CL/F, and elimination half-life were used to assess the effects of milk thistle, black cohosh, rifampin, and clarithromycin on digoxin pharmacokinetics. Rifampin produced significant reductions (p<0.01) in AUC(0-3), AUC(0-24) and Cmax, while clarithromycin increased these parameters significantly (p<0.01). Significant changes in digoxin half-life and CL/F were also observed with clarithromycin. No statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either milk thistle or black cohosh, although digoxin AUC(0-3) and AUC(0-24) approached significance (p=0.06) following milk thistle administration. When compared to rifampin and clarithromycin, supplementation with these specific formulations of milk thistle or black cohosh did not appear to affect digoxin pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo.


Key words: ABC transporters, clinical pharmacokinetics, drug interactions, drug-drug interactions, in vivo probes, p-glycoprotein, pharmacogenetics, pharmacokinetics


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