Article

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

Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Drug Metabolism and Disposition (Impact Factor: 3.25). 01/2006; 34(1):69-74. DOI: 10.1124/dmd.105.006312
Source: PubMed

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.

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    • "However, these in vitro observations generally have not manifested clinically. For example, two healthy volunteer studies demonstrated no interaction between the CYP3A probe substrate midazolam and one silymarin product (Gurley et al., 2004, 2006), whereas another study demonstrated a different silymarin product to significantly increase the systemic exposure to the CYP2C9/3A substrate losartan (Han et al., 2009). This discrepancy may be attributed to large variation in relative composition between herbal products. "
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    ABSTRACT: Despite increasing recognition of potential untoward interactions between herbal products and conventional medications, a standard system for prospective assessment of these interactions remains elusive. This information gap was addressed by evaluating the drug interaction liability of the model herbal product milk thistle (Silybum marianum) with the CYP3A4/5 probe substrate midazolam. The inhibitory effects of commercially available milk thistle extracts and isolated constituents on midazolam 1'-hydroxylation were screened using human liver and intestinal microsomes. Relative to vehicle, the extract silymarin and constituents silybin A, isosilybin A, isosilybin B, and silychristin at 100 μM demonstrated >50% inhibition of CYP3A4/5 activity with at least one microsomal preparation, prompting IC50 determination. The IC50s for isosilybin B and silychristin were ~60, and 90 μM, respectively, whereas those for the remaining constituents were >100 μM. Extracts and constituents that contained the 1,4-dioxane moiety demonstrated a >1.5-fold shift in IC50 when tested as potential mechanism-based inhibitors. The semi-purified extract, silibinin, and the two associated constituents (silybin A, silybin B) demonstrated mechanism-based inhibition of recombinant CYP3A4 (KI ≈100 μM; kinact ≈0.20 min(-1)) but not microsomal CYP3A4/5 activity. The maximum predicted increase in midazolam AUC using the static mechanistic equation and recombinant CYP3A4 data was 1.75-fold, which may necessitate clinical assessment. Evaluation of the interaction liability of single herbal product constituents, in addition to commercially available extracts, will enable elucidation of mechanisms underlying potential clinically significant herb-drug interactions. Application of this framework to other herbal products would permit predictions of herb-drug interactions and assist in prioritizing clinical evaluation.
    Preview · Article · Jun 2013 · Drug metabolism and disposition: the biological fate of chemicals
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    • "Those that have been conducted focus primarily on St. John's wort and its effect on digoxin(Johne et al., 1999) or fexofenadine pharmacokinetics(Dresser et al., 2003). More recently the effects of hawthorn(Tankanow et al., 2003), milk thistle, and black cohosh(Gurley et al, 2006) on digoxin pharmacokinetics were tested, and found to be clinically insignificant. Due to the significant underreporting of drug interactions and adverse events associated with dietary supplements, more clinical studies are needed to better evaluate the interaction potential of botanical supplements with P-gp substrates. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Jan 2006 · Drug Metabolism and Disposition
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    ABSTRACT: Due in part to the increased consumption of herbal products on a global scale, a sharp rise in the reported number of both in vitro and in vivo interactions of herbals with prescription drugs that are metabolized by cytochrome P450 (CYP) enzymes has been observed. Popular products such as ginseng, saw palmetto and St. John's wort have demonstrated potent in vitro inhibition or induction of CYP activity. While reports of in vivo interactions are not as numerous, natural products such as garlic, goldenseal and grapefruit juice have shown the potential to affect CYP activity in vivo. As the wide-spread use of herbal and alternative medicines continues, an increased awareness on the part of the research and medical communities should afford safer use of these products in the future.
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