title: Effect of milk thistle (Silybum marianum) and black cohosh (Cimicifuga racemosa) supplementation on digoxin pharmacokinetics in humans.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. gurleybillyj@uams.edu
authors.forename: Bill J
authors.initials: BJ
authors.lastname: Gurley
authors.forename: Gary W
authors.initials: GW
authors.lastname: Barone
authors.forename: D Keith
authors.initials: DK
authors.lastname: Williams
authors.forename: Julie
authors.initials: J
authors.lastname: Carrier
authors.forename: Philip
authors.initials: P
authors.lastname: Breen
authors.forename: C Ryan
authors.initials: CR
authors.lastname: Yates
authors.forename: Peng-fei
authors.initials: PF
authors.lastname: Song
authors.forename: Martha A
authors.initials: MA
authors.lastname: Hubbard
authors.forename: Yudong
authors.initials: Y
authors.lastname: Tong
authors.forename: Sreekhar
authors.initials: S
authors.lastname: Cheboyina
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D031885:Cimicifuga; D017291:Clarithromycin / Q000008:administration & dosage / Q000493:pharmacokinetics; D019587:Dietary Supplements; D004077:Digoxin / Q000037:antagonists & inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D005260:Female; D019450:Genes, MDR / Q000235:genetics; D006207:Half-Life; D006239:Haplotypes / Q000235:genetics; D041743:Herb-Drug Interactions; D006801:Humans; D008297:Male; D020944:Silybum marianum; D028321:Plant Preparations / Q000008:administration & dosage / Q000494:pharmacology*; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000652:urine
chemical_list: D028321:Plant Preparations; D004077:Digoxin; D017291:Clarithromycin; D012293:Rifampin