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Drug Metabolism and Disposition Fast Forward
First published on October 12, 2005; DOI: 10.1124/dmd.105.006312

0090-9556/06/3401-69-74$20.00
DMD 34:69-74, 2006

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EFFECT OF MILK THISTLE (SILYBUM MARIANUM) AND BLACK COHOSH (CIMICIFUGA RACEMOSA) SUPPLEMENTATION ON DIGOXIN PHARMACOKINETICS IN HUMANS

Bill J. Gurley, Gary W. Barone, D. Keith Williams, Julie Carrier, Philip Breen, C. Ryan Yates, Peng-fei Song, Martha A. Hubbard, Yudong Tong, and Sreekhar Cheboyina

Department of Pharmaceutical Sciences (B.J.G., P.B., M.A.H., Y.T.), Department of Surgery (G.W.B.), and Department of Biometry, University of Arkansas for Medical Sciences, Little Rock, Arkansas (D.K.W.); Department of Biological and Agricultural Engineering, University of Arkansas, Fayetteville, Arkansas (J.C.); Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, Tennessee (C.R.Y., P.S.); and Department of Pharmaceutics, University of Mississippi, University, Mississippi (S.C.).

Phytochemical-mediated modulation of P-glycoprotein (P-gp) and other drug transporters may underlie many herb-drug interactions. Serial serum 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 serum concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the serum concentration time curves from 0 to 3 h (AUC(0–3)), AUC(0–24), Cmax, apparent oral clearance of digoxin (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, whereas 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 with 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.

Address correspondence to: Dr. Bill J. Gurley, University of Arkansas for Medical Sciences, College of Pharmacy, Department of Pharmaceutical Sciences, 4301 W. Markham St., Slot 522-3, Little Rock, AR 72205. E-mail: gurleybillyj{at}uams.edu




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