Influence of Panax ginseng on cytochrome P450 (CYP)3A and P-glycoprotein (P-gp) activity in healthy participants

Christine Y Malati, Sarah M Robertson, Jennifer D Hunt, Cheryl Chairez, Raul M Alfaro, Joseph A Kovacs, Scott R Penzak, Christine Y Malati, Sarah M Robertson, Jennifer D Hunt, Cheryl Chairez, Raul M Alfaro, Joseph A Kovacs, Scott R Penzak

Abstract

A number of herbal preparations have been shown to interact with prescription medications secondary to modulation of cytochrome P450 (CYP) and/or P-glycoprotein (P-gp). The purpose of this study was to determine the influence of Panax ginseng on CYP3A and P-gp function using the probe substrates midazolam and fexofenadine, respectively. Twelve healthy participants (8 men) completed this open-label, single-sequence pharmacokinetic study. Healthy volunteers received single oral doses of midazolam 8 mg and fexofenadine 120 mg, before and after 28 days of P ginseng 500 mg twice daily. Midazolam and fexofenadine pharmacokinetic parameter values were calculated and compared before and after P ginseng administration. Geometric mean ratios (postginseng/preginseng) for midazolam area under the concentration-time curve from zero to infinity (AUC(0-∞)), half-life (t(1/2)), and maximum concentration (C(max)) were significantly reduced at 0.66 (0.55-0.78), 0.71 (0.53-0.90), and 0.74 (0.56-0.93), respectively. Conversely, fexofenadine pharmacokinetics were unaltered by P ginseng administration. Based on these results, P ginseng appeared to induce CYP3A activity in the liver and possibly the gastrointestinal tract. Patients taking P ginseng in combination with CYP3A substrates with narrow therapeutic ranges should be monitored closely for adequate therapeutic response to the substrate medication.

Conflict of interest statement

Declaration of interest: The authors have no financial conflicts of interest or other commercial relationships to declare. No outside statistical or editorial assistance was provided to the authors. No official support or endorsement of this article by the US Food and Drug Administration is intended or should be inferred.

Figures

Figure 1
Figure 1
Midazolam concentrations (±SEM) before- and after 28 days of Panax ginseng
Figure 2
Figure 2
Fexofenadine concentrations (±SEM) before- and after 28 days of Panax ginseng administration

References

    1. Eisenberg DM, Daivs RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990–1997: results of a follow-up national survey. JAMA. 1998;280:1569–1575.
    1. Tindle HA, Davis RB, Phillips RS, Eisenberg DM. Trends in use of complementary and alternative medicine use by US adults: 1997–2002. Altern Ther Health Med. 2005;11:42–49.
    1. Robertson SM, Davey RT, Voell J, et al. Effect of Ginkgo biloba extract on lopinavir, midazolam and fexofenadine pharmacokinetics in healthy subjects. Curr Med Res Opin. 2008;24:591–599.
    1. Penzak SR, Robertson SM, Hunt JD, et al. Echinacea purpurea significantly induces cytochrome P450 3A activity but does not alter lopinavir-ritonavir exposure in healthy subjects. Pharmacotherapy. 2010;30:797–805.
    1. Borrelli F, Izzo AA. Herb-drug interactions with St John’s wort (Hypericum perforatum): an update on clinical observations. AAPS J. 2009;11:710–727.
    1. Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs: an updated systematic review. Drugs. 2009;69:1777–1798.
    1. Gurley BJ, Gardner SF, Hubbard MA, et al. Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans. Clin Pharmacol Ther. 2002;72:276–287.
    1. Guengerich FP. Cytochrome P-450 3A4: regulation and role in drug metabolism. Annu Rev Pharmacol Toxicol. 1999;39:1–17.
    1. Wrighton SA, Stevens JC. The human hepatic cytochromes P450 involved in drug metabolism. Crit Rev Toxicol. 1992;22:1–21.
    1. Coon JT, Ernst E. Panax ginseng: a systematic review of adverse effects and drug interactions. Drug Saf. 2002;25:323–344.
    1. Christensen LP. Ginsenosides chemistry, biosynthesis, analysis, and potential health effects. Adv Food Nutr Res. 2009;55:1–99.
    1. Chen CF, Chiou WF, Zhang JT, et al. Comparison of the pharmacological effects of Panax ginseng and Panax quinquefolium. Acta Pharmacol Sin. 2008;29:1103–1108.
    1. Gurley Bill J, Gardner SF, Hubbard MA, et al. Clinical Assessment of effects of botanical supplementation on cytochrome P450 phenotypes in the elderly. Drugs Aging. 2005;22:525–539.
    1. Anderson GD, Rosito G, Mohustsy MA, Elmer GW. Drug interaction potential of soy extract and Panax ginseng. J Clin Pharmacol. 2003;43:643–648.
    1. Gorski CJ, Huang SM, Pinto A, et al. The effect of Echinacea (Echinacea purpurea root) on cytochrome P450 activity in vivo. Clin Pharmacol Ther. 2004;75:89–100.
    1. Budzinski JW, Foster BC, Vandenhoek S, Arnason JT. An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures. Phytomedicine. 2000;7:273–282.
    1. He N, Edeki TI. Effects of ginseng and Ginkgo biloba components on CYP3A4 mediated testosterone 6beta-hydroxylation in human liver microsomes [abstract] Clin Pharmacol Ther. 2003;73:50, Abstract PII-81.
    1. Henderson GL, Harkey MR, Gershwin ME, Hackman RM, Stern JS, Stresser DM. Effects of ginseng components on c-DNA-expressed cytochrome P450 enzyme catalytic activity. Life Sci. 1999;65:209–214.
    1. Smith M, Lin KM, Zheng YP. An open trial of nifedipine-herb interactions: nifedipine with St. John’s wort, ginseng, or ginkgo biloba [abstract] Clin Pharmacol Ther. 2001;69:86, Abstract PIII-89.
    1. Dresser GK, Bailey DG, Leake BF, et al. Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine. Clin Pharmacol Ther. 2002;71:11–20.
    1. Kashuba ADM, Bertino JS., Jr . Mechanisms of Drug interactions I: Absorption, Metabolism and Excretion. In: Piscitelli SC, Rodvold KA, editors. Drug Interactions in Infectious Diseases. 2. Totowa, NJ: Human Press; 2005. pp. 13–39.
    1. Liu Y, Zhang JW, Li W, et al. Ginsenoside metabolites, rather than naturally ocurribg ginsenosides, lead to inhibition of human cytochrome P450 enzymes. Toxicol Sci. 2006;91:356–64.
    1. Hao H, Ba Q, Yin J, et al. Deglycosylated ginsenosides are more potent inducers of CYP1A1, CYP1A2, and CYP3A4 expression in HepG2 cells than glycosylated ginsenosides. Drug Metab Pharmacokinet. 2010 Dec 17; [Epub ahead of print]
    1. US Department of Health and Human Services. Food and Drug Administration. Guidance for Industry: Drug interaction studies – study design, data analysis, and implications for dosing and labeling. 2006 Sep; Available from: .
    1. Piscitelli SC, Burstein AH, Welden N, Gallicano KD, Falloon J. The effect of garlic supplements on the pharmacokinetics of saquinavir. Clin Infect Dis. 2002;34:234–8.
    1. Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J. Indinavir concentrations and St. John’s wort Lancet. 2000;355:547–48.
    1. Streetman DS, Bertino JS, Nafziger AN. Phenotyping of drug-metabolizing enzymes in adults: a review of in-vivo cyctochrome P450 phenotyping probes. Pharmacogenetics. 2000;10:187–216.
    1. Rogers JF, Nafziger AN, Kashuba AD, et al. Single plasma concentrations of 1′-hydroxymidazolam or the ratio of 1′-hydroxymidazolam: midazolam do not predict midazolam clearance in healthy subjects. J Clin Pharmacol. 2002;42:1079–1082.
    1. Eap CB, Buclin T, Cucchia G, et al. Oral administration of a low dose of midazolam (75 microg) as an in vivo probe for CYP3A activity. Eur J Clin Pharmacol. 2004;60:237–246.
    1. Lin YS, Lockwood GF, Graham MA, et al. In-vivo phenotyping for CYP3A by a single-point determination of midazolam plasma concentration. Pharmacogenetics. 2001;11:781–791.
    1. Nafziger AN, Bertino JS., Jr Low hepatic cytochrome P450 3A activity is a risk for corticosteroid-induced osteonecrosis. Clin Pharmacol Ther. 2007;82:379.
    1. Hunt CM, Watkins PB, Saenger P, Stave GM, Barlascini N, Watlington CO, et al. Heterogeneity of CYP3A isoforms metabolizing erythromycin and cortisol. Clin Pharmacol Ther. 1992;51:18–23.
    1. Kinirons MT, O’Shea D, Downing TE, Fitzwilliam AT, Joellenbeck L, Groopman JD, et al. Absence of correlations among three putative in-vivo probes of human cytochrome P-4503A4 activity in young healthy men. Clin Pharmacol Ther. 1993;54:621–629.
    1. Watkins PB, Turgeon DK, Saenger P, Lown KS, Kolars JC, Hamilton T, et al. Comparisons of urinary 6-beta-cortisol and the erythromycin breath test as measures of hepatic P450IIIA (CYP3A) activity. Clin Pharmacol Ther. 1992;52:265–273.
    1. Ma JD, Tsunoda SM, Bertino JS, Trivedi M, Beale KK, Nafziger AN. Evaluation of in vivo p-glycoprotein phenotyping probes: A need for validation. Clin Pharmacokinet. 2010;49:223–237.
    1. Cvetkovic M, Leake B, Fromm MF, Wilkinson GR, Kim RB. OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metab Dispos. 1999;27:866–871.
    1. Putnam WS, Ramanathan S, Pan L, Takahashi LH, Benet LZ. Functional characterization of monocarboxylic acid, large neutral amino acid, bile acid and peptide transporters, and P-glycoprotein in MDCK and Caco-2 cells. J Pharm Sci. 2002;91:2622–2635.
    1. Perloff MD, von Moltke LL, Greenblatt DJ. Fexofenadine transport in Caco-2 cells: inhibition with verapamil and ritonavir. J Clin Pharmacol. 2002;42:1269–1274.
    1. Gupta S, Banfield C, Kantesaria B, Marino M, Clement R, Affrime M, Batra V. Pharmacokinetic and safety profile of desloratadine and fexofenadine when coadministered with azithromycin: a randomized, placebo-controlled, parallel-group study. Clin Ther. 2001;23:451–466.
    1. Hamman MA, Bruce MA, Haehner-Daniels BD, Hall SD. The effect of rifampin administration on the disposition of fexofenadine. Clin Pharmacol Ther. 2001;69:114–121.
    1. Yasui-Furukori N, Uno T, Sugawara K, Tateishi T. Different effects of three transporting inhibitors, verapamil, cimetidine, and probenecid, on fexofenadine pharmacokinetics. Clin Pharmacol Ther. 2005;77:17–23.
    1. Shimizu M, Uno T, Sufawara K, Tateishi T. Effects of itraconazole and diltiazem on the pharmacokinetics of fexofenadine, a substrate of P-glycoprotein. Brit J Clin Pharmacol. 2006;61:538–544.
    1. Nozawa T, Imai K, Nezu J, et al. Functional characterization of pH-sensitive organic anion transporting polypeptide OATP-B in human. J Pharmacol Exp Ther. 2004;308:438–445.
    1. Matsushima S, Maeda K, Ishiguro N, et al. Investigation of the inhibitory effects of various drugs on the hepatic uptake of fexofenadine in humans. Drug Metab Dispos. 2008;36:663–669.
    1. Shimizu M, Fuse K, Okudaira K, et al. Contribution of OATP (organic anion-transporting polypeptide) family transporters to the hepatic uptake of fexofenadine in humans. Drug Metab Dispos. 2005;33:1477–1481.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj