Abstract
Phytochemical-mediated modulation of P-glycoprotein (P-gp) and other drug transporters may give rise to many herb-drug interactions. Serial plasma concentration-time profiles of the P-gp substrate, digoxin, were used to determine whether supplementation with goldenseal or kava kava modified P-gp activity in vivo. Twenty healthy volunteers were randomly assigned to receive a standardized goldenseal (3210 mg daily) or kava kava (1227 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 (Lanoxin, 0.5 mg) was administered p.o. before and at the end of each supplementation and control period. Serial digoxin plasma concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the curve (AUC)(0–3), AUC(0–24), Cmax, CL/F, and elimination half-life were used to assess the effects of goldenseal, kava kava, rifampin, and clarithromycin on digoxin pharmacokinetics. Rifampin produced significant reductions (p < 0.01) in AUC(0–3), AUC(0–24), CL/F, t1/2, and Cmax, whereas clarithromycin increased these parameters significantly (p < 0.01). With the exception of goldenseal's effect on Cmax (14% increase), no statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either goldenseal or kava kava. When compared with rifampin and clarithromycin, supplementation with these specific formulations of goldenseal or kava kava did not appear to affect digoxin pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo.
Footnotes
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This work is supported by the National Institutes of Health/National Institute of General Medical Sciences under Grant R01 GM71322 and by National Institutes of Health/National Center for Research Resources to the General Clinical Research Center of the University of Arkansas for Medical Sciences under Grant M01 RR14288.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.106.012708.
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ABBREVIATIONS: P450, cytochrome P450; P-gp, P-glycoprotein; AST, aspartate aminotransferase; ALT, alanine aminotransferase; HPLC, high-performance liquid chromatography; AUC, area under the curve; ke, elimination rate constant; CL/F, apparent oral clearance.
- Received September 1, 2006.
- Accepted October 27, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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