Relevance of in vitro and clinical data for predicting CYP3A4-mediated herb–drug interactions in cancer patients

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    Andrew K.L. Goey
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    Kim D. Mooiman
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    Jos H. Beijnen
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    Slotervaart Hospital/The Netherlands Cancer Institute, Department of Pharmacy & Pharmacology, Louwesweg 6, 1066 EC Amsterdam, The Netherlands
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    Jan H.M. Schellens
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    The Netherlands Cancer Institute, Division of Clinical Pharmacology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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  • Irma Meijerman
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Published:February 11, 2013DOI:https://doi.org/10.1016/j.ctrv.2012.12.008

      Abstract

      The use of complementary and alternative medicines (CAM) by cancer patients is increasing. Concomitant use of CAM and anticancer drugs could lead to serious safety issues in patients. CAM have the potential to cause pharmacokinetic interactions with anticancer drugs, leading to either increased or decreased plasma levels of anticancer drugs. This could result in unexpected toxicities or a reduced efficacy. Significant pharmacokinetic interactions have already been shown between St. John’s Wort (SJW) and the anticancer drugs imatinib and irinotecan.
      Most pharmacokinetic CAM–drug interactions, involve drug metabolizing cytochrome P450 (CYP) enzymes, in particular CYP3A4. The effect of CAM on CYP3A4 activity and expression can be assessed in vitro. However, no data have been reported yet regarding the relevance of these in vitro data for the prediction of CAM–anticancer drug interactions in clinical practice. To address this issue, a literature research was performed to evaluate the relevance of in vitro data to predict clinical effects of CAM frequently used by cancer patients: SJW, milk thistle, garlic and Panax ginseng (P. ginseng). Furthermore, in clinical studies the sensitive CYP3A4 substrate probe midazolam is often used to determine pharmacokinetic interactions. Results of these clinical studies with midazolam are used to predict pharmacokinetic interactions with other drugs metabolized by CYP3A4. Therefore, this review also explored whether clinical trials with midazolam are useful to predict clinical pharmacokinetic CAM–anticancer drug interactions.
      In vitro data of SJW have shown CYP3A4 inhibition after short-term exposure and induction after long-term exposure. In clinical studies using midazolam or anticancer drugs (irinotecan and imatinib) as known CYP3A4 substrates in combination with SJW, decreased plasma levels of these drugs were observed, which was expected as a consequence of CYP3A4 induction. For garlic, no effect on CYP3A4 has been shown in vitro and also in clinical studies garlic did not affect the pharmacokinetics of both midazolam and docetaxel.
      Milk thistle and P. ginseng predominantly showed CYP3A4 inhibition in vitro. However, in clinical studies these CAM did not cause significant pharmacokinetic interactions with midazolam, irinotecan, docetaxel and imatinib. Most likely, factors as poor pharmaceutical availability, solubility and bioavailability contribute to the lack of significant clinical interactions.
      In conclusion, in vitro data are useful as a first indication for potential pharmacokinetic drug interactions with CAM. However, the discrepancies between in vitro and clinical results for milk thistle and P. ginseng show that clinical studies are required for confirmation of potential interactions. At last, midazolam as a model substrate for CYP3A4, has convincingly shown to correctly predict clinical interactions between CAM and anticancer drugs.

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      References

        • Sewitch M.J.
        • Rajput Y.
        A literature review of complementary and alternative medicine use by colorectal cancer patients.
        Complement Ther Clin Pract. 2010; 16: 52-56
        • Bishop F.L.
        • Rea A.
        • Lewith H.
        • Chan Y.K.
        • Saville J.
        • Prescott P.
        • et al.
        Complementary medicine use by men with prostate cancer: a systematic review of prevalence studies.
        Prostate Cancer Prostatic Dis. 2011; 14: 1-13
        • Bishop F.L.
        • Prescott P.
        • Chan Y.K.
        • Saville J.
        • von Elm E.
        • Lewith G.T.
        Prevalence of complementary medicine use in pediatric cancer: a systematic review.
        Pediatrics. 2010; 125: 768-776
        • Sparreboom A.
        • Cox M.C.
        • Acharya M.R.
        • Figg W.D.
        Herbal remedies in the United States: potential adverse interactions with anticancer agents.
        J Clin Oncol. 2004; 22: 2489-2503
        • Tascilar M.
        • de Jong F.A.
        • Verweij J.
        • Mathijssen R.H.
        Complementary and alternative medicine during cancer treatment: beyond innocence.
        Oncologist. 2006; 11: 732-741
        • Werneke U.
        • Earl J.
        • Seydel C.
        • Horn O.
        • Crichton P.
        • Fannon D.
        Potential health risks of complementary alternative medicines in cancer patients.
        Br J Cancer. 2004; 90: 408-413
        • Pal D.
        • Mitra A.K.
        MDR- and CYP3A4-mediated drug–herbal interactions.
        Life Sci. 2006; 78: 2131-2145
        • Gouws C.
        • Steyn D.
        • Du Plessis L.
        • Steenekamp J.
        • Hamman J.H.
        Combination therapy of Western drugs and herbal medicines: recent advances in understanding interactions involving metabolism and efflux.
        Expert Opin Drug Metab Toxicol. 2012; 8: 973-984
        • Unger M.
        Pharmacokinetic drug interactions between anticancer therapeutics and drugs of complementary medicine: mechanisms and clinical relevance.
        Forsch Komplementmed. 2011; 18: 213-218
        • Mathijssen R.H.
        • Verweij J.
        • de Bruijn P.
        • Loos W.J.
        • Sparreboom A.
        Effects of St. John’s wort on irinotecan metabolism.
        J Natl Cancer Inst. 2002; 94: 1247-1249
        • Smith P.
        • Bullock J.M.
        • Booker B.M.
        • Haas C.E.
        • Berenson C.S.
        • Jusko W.J.
        The influence of St. John’s wort on the pharmacokinetics and protein binding of imatinib mesylate.
        Pharmacotherapy. 2004; 24: 1508-1514
        • Frye R.F.
        • Fitzgerald S.M.
        • Lagattuta T.F.
        • Hruska M.W.
        • Egorin M.J.
        Effect of St John’s wort on imatinib mesylate pharmacokinetics.
        Clin Pharmacol Ther. 2004; 76: 323-329
        • He S.M.
        • Yang A.K.
        • Li X.T.
        • Du Y.M.
        • Zhou S.F.
        Effects of herbal products on the metabolism and transport of anticancer agents.
        Expert Opin Drug Metab Toxicol. 2010; 6: 1195-1213
        • Martignoni M.
        • Groothuis G.M.
        • de Kanter R.
        Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction.
        Expert Opin Drug Metab Toxicol. 2006; 2: 875-894
        • Foti R.S.
        • Rock D.A.
        • Wienkers L.C.
        • Wahlstrom J.L.
        Selection of alternative CYP3A4 probe substrates for clinical drug interaction studies using in vitro data and in vivo simulation.
        Drug Metab Dispos. 2010; 38: 981-987
      1. NoAb BioDiscoveries. Metabolic stability – microsomes. <http://www.noabbiodiscoveries.com/assays/invitro/metabolic_stability_subcellular.pdf/>; 2012 [accessed 26.06.2012].

      2. European Medicines Agency. Guideline on the investigation of drug interactions. <http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/05/WC500090112.pdf/>; 2012 [accessed 25.06.2012].

        • Vogel H.G.
        • Hock F.J.
        • Maas J.
        • Mayer D.
        Drug discovery and evaluation: safety and pharmacokinetic assays.
        Springer, New York2006
        • Bhogal R.H.
        • Hodson J.
        • Bartlett D.C.
        • Weston C.J.
        • Curbishley S.M.
        • Haughton E.
        • et al.
        Isolation of primary human hepatocytes from normal and diseased liver tissue: a one hundred liver experience.
        PLoS One. 2011; 6: e18222
        • Bjornsson T.D.
        • Callaghan J.T.
        • Einolf H.J.
        • Fischer V.
        • Gan L.
        • Grimm S.
        • et al.
        The conduct of in vitro and in vivo drug–drug interaction studies: a PhRMA perspective.
        J Clin Pharmacol. 2003; 43: 443-469
        • Parkinson A.
        • Kazmi F.
        • Buckley D.B.
        • Yerino P.
        • Ogilvie B.W.
        • Paris B.L.
        System-dependent outcomes during the evaluation of drug candidates as inhibitors of cytochrome P450 (CYP) and uridine diphosphate glucuronosyltransferase (UGT) enzymes: human hepatocytes versus liver microsomes versus recombinant enzymes.
        Drug Metab Pharmacokinet. 2010; 25: 16-27
      3. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation (CDER), Center for Biologics Evaluation and Research (CBER). Guidance for industry: drug interaction studies – study design, data analysis, and implications for dosing and labeling. <http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf/>; 2012 [accessed 25.06.2012].

        • Na D.H.
        • Ji H.Y.
        • Park E.J.
        • Kim M.S.
        • Liu K.H.
        • Lee H.S.
        Evaluation of metabolism-mediated herb–drug interactions.
        Arch Pharm Res. 2011; 34: 1829-1842
      4. Particle Sciences. Mass spectrometry in bioanalysis. <http://www.particlesciences.com/docs/technical_briefs/TB_4.pdf/>; 2009 [accessed 25.06.2009].

        • Stresser D.M.
        • Blanchard A.P.
        • Turner S.D.
        • Erve J.C.
        • Dandeneau A.A.
        • Miller V.P.
        • et al.
        Substrate-dependent modulation of CYP3A4 catalytic activity: analysis of 27 test compounds with four fluorometric substrates.
        Drug Metab Dispos. 2000; 28: 1440-1448
        • Moore L.B.
        • Goodwin B.
        • Jones S.A.
        • Wisely G.B.
        • Serabjit-Singh C.J.
        • Willson T.M.
        • et al.
        St. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor.
        Proc Natl Acad Sci USA. 2000; 97: 7500-7502
        • Harmsen S.
        • Koster A.S.
        • Beijnen J.H.
        • Schellens J.H.
        • Meijerman I.
        Comparison of two immortalized human cell lines to study nuclear receptor-mediated CYP3A4 induction.
        Drug Metab Dispos. 2008; 36: 1166-1171
      5. Health Canada. Therapeutic products programme: guidance document: drug–drug interactions: studies in vitro and in vivo 2000. <http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/drug_medi_int-eng.pdf/>; 2012 [accessed 25.06.2012].

        • Kronbach T.
        • Mathys D.
        • Umeno M.
        • Gonzalez F.J.
        • Meyer U.A.
        Oxidation of midazolam and triazolam by human liver cytochrome P450IIIA4.
        Mol Pharmacol. 1989; 36: 89-96
        • Gurley B.J.
        • Gardner S.F.
        • Hubbard M.A.
        • Williams D.K.
        • Gentry W.B.
        • Cui Y.
        • et al.
        Clinical assessment of effects of botanical supplementation on cytochrome P450 phenotypes in the elderly: St John’s wort, garlic oil, Panax ginseng and Ginkgo biloba.
        Drugs Aging. 2005; 22: 525-539
        • Gurley B.J.
        • Gardner S.F.
        • Hubbard M.A.
        • Williams D.K.
        • Gentry W.B.
        • Cui Y.
        • et al.
        Cytochrome P450 phenotypic ratios for predicting herb–drug interactions in humans.
        Clin Pharmacol Ther. 2002; 72: 276-287
        • Zhu B.
        • Ou-Yang D.S.
        • Cheng Z.N.
        • Huang S.L.
        • Zhou H.H.
        Single plasma sampling to predict oral clearance of CYP3A probe midazolam.
        Acta Pharmacol Sin. 2001; 22: 634-638
        • Gutmann H.
        • Poller B.
        • Buter K.B.
        • Pfrunder A.
        • Schaffner W.
        • Drewe J.
        Hypericum perforatum: which constituents may induce intestinal MDR1 and CYP3A4 mRNA expression?.
        Planta Med. 2006; 72: 685-690
        • Hokkanen J.
        • Tolonen A.
        • Mattila S.
        • Turpeinen M.
        Metabolism of hyperforin, the active constituent of St. John’s wort, in human liver microsomes.
        Eur J Pharm Sci. 2011; 42: 273-284
        • Obach R.S.
        Inhibition of human cytochrome P450 enzymes by constituents of St. John’s Wort, an herbal preparation used in the treatment of depression.
        J Pharmacol Exp Ther. 2000; 294: 88-95
        • Hansen T.S.
        • Nilsen O.G.
        In vitro CYP3A4 metabolism: inhibition by Echinacea purpurea and choice of substrate for the evaluation of herbal inhibition.
        Basic Clin Pharmacol Toxicol. 2008; 103: 445-449
        • Patel J.
        • Buddha B.
        • Dey S.
        • Pal D.
        • Mitra A.K.
        In vitro interaction of the HIV protease inhibitor ritonavir with herbal constituents: changes in P-gp and CYP3A4 activity.
        Am J Ther. 2004; 11: 262-277
        • Henderson G.L.
        • Harkey M.R.
        • Gershwin M.E.
        • Hackman R.M.
        • Stern J.S.
        • Stresser D.M.
        Effects of ginseng components on c-DNA-expressed cytochrome P450 enzyme catalytic activity.
        Life Sci. 1999; 65: PL209-PL214
        • Komoroski B.J.
        • Zhang S.
        • Cai H.
        • Hutzler J.M.
        • Frye R.
        • Tracy T.S.
        • et al.
        Induction and inhibition of cytochromes P450 by the St. John’s wort constituent hyperforin in human hepatocyte cultures.
        Drug Metab Dispos. 2004; 32: 512-518
        • Komoroski B.J.
        • Parise R.A.
        • Egorin M.J.
        • Strom S.C.
        • Venkataramanan R.
        Effect of the St. John’s wort constituent hyperforin on docetaxel metabolism by human hepatocyte cultures.
        Clin Cancer Res. 2005; 11: 6972-6979
        • Wang Z.
        • Gorski J.C.
        • Hamman M.A.
        • Huang S.M.
        • Lesko L.J.
        • Hall S.D.
        The effects of St John’s wort (Hypericum perforatum) on human cytochrome P450 activity.
        Clin Pharmacol Ther. 2001; 70: 317-326
        • Hall S.D.
        • Wang Z.
        • Huang S.M.
        • Hamman M.A.
        • Vasavada N.
        • Adigun A.Q.
        • et al.
        The interaction between St John’s wort and an oral contraceptive.
        Clin Pharmacol Ther. 2003; 74: 525-535
        • Dresser G.K.
        • Schwarz U.I.
        • Wilkinson G.R.
        • Kim R.B.
        Coordinate induction of both cytochrome P4503A and MDR1 by St John’s wort in healthy subjects.
        Clin Pharmacol Ther. 2003; 73: 41-50
        • Xie R.
        • Tan L.H.
        • Polasek E.C.
        • Hong C.
        • Teillol-Foo M.
        • Gordi T.
        • et al.
        CYP3A and P-glycoprotein activity induction with St. John’s Wort in healthy volunteers from 6 ethnic populations.
        J Clin Pharmacol. 2005; 45: 352-356
        • Mueller S.C.
        • Majcher-Peszynska J.
        • Uehleke B.
        • Klammt S.
        • Mundkowski R.G.
        • Miekisch W.
        • et al.
        The extent of induction of CYP3A by St. John’s wort varies among products and is linked to hyperforin dose.
        Eur J Clin Pharmacol. 2006; 62: 29-36
        • Mueller S.C.
        • Majcher-Peszynska J.
        • Mundkowski R.G.
        • Uehleke B.
        • Klammt S.
        • Sievers H.
        • et al.
        No clinically relevant CYP3A induction after St. John’s wort with low hyperforin content in healthy volunteers.
        Eur J Clin Pharmacol. 2009; 65: 81-87
        • van Erp N.P.
        • Baker S.D.
        • Zhao M.
        • Rudek M.A.
        • Guchelaar H.J.
        • Nortier J.W.
        • et al.
        Effect of milk thistle (Silybum marianum) on the pharmacokinetics of irinotecan.
        Clin Cancer Res. 2005; 11: 7800-7806
        • Lee L.S.
        • Andrade A.S.
        • Flexner C.
        Interactions between natural health products and antiretroviral drugs: pharmacokinetic and pharmacodynamic effects.
        Clinical Infect Dis. 2006; 43: 1052-1059
        • Saller R.
        • Meier R.
        • Brignoli R.
        The use of silymarin in the treatment of liver diseases.
        Drugs. 2001; 61: 2035-2063
        • Kroll D.J.
        • Shaw H.S.
        • Oberlies N.H.
        Milk thistle nomenclature: why it matters in cancer research and pharmacokinetic studies.
        Integr Cancer Ther. 2007; 6: 110-119
        • Etheridge A.S.
        • Black S.R.
        • Patel P.R.
        • So J.
        • Mathews J.M.
        An in vitro evaluation of cytochrome P450 inhibition and P-glycoprotein interaction with goldenseal, Ginkgo biloba, grape seed, milk thistle, and ginseng extracts and their constituents.
        Planta Med. 2007; 73: 731-741
        • Doehmer J.
        • Tewes B.
        • Klein K.U.
        • Gritzko K.
        • Muschick H.
        • Mengs U.
        Assessment of drug-drug interaction for silymarin.
        Toxicol In Vitro. 2008; 22: 610-617
        • Zuber R.
        • Modriansky M.
        • Dvorak Z.
        • Rohovsky P.
        • Ulrichova J.
        • Simanek V.
        • et al.
        Effect of silybin and its congeners on human liver microsomal cytochrome P450 activities.
        Phytother Res. 2002; 16: 632-638
        • Jancova P.
        • Anzenbacherova E.
        • Papouskova B.
        • Lemr K.
        • Luzna P.
        • Veinlichova A.
        • et al.
        Silybin is metabolized by cytochrome P450 2C8 in vitro.
        Drug Metab Dispos. 2007; 35: 2035-2039
        • Beckmann-Knopp S.
        • Rietbrock S.
        • Weyhenmeyer R.
        • Bocker R.H.
        • Beckurts K.T.
        • Lang W.
        • et al.
        Inhibitory effects of silibinin on cytochrome P-450 enzymes in human liver microsomes.
        Pharmacol Toxicol. 2000; 86: 250-256
        • Venkataramanan R.
        • Ramachandran V.
        • Komoroski B.J.
        • Zhang S.
        • Schiff P.L.
        • Strom S.C.
        Milk thistle, a herbal supplement, decreases the activity of CYP3A4 and uridine diphosphoglucuronosyl transferase in human hepatocyte cultures.
        Drug Metab Dispos. 2000; 28: 1270-1273
        • Sridar C.
        • Goosen T.C.
        • Kent U.M.
        • Williams J.A.
        • Hollenberg P.F.
        Silybin inactivates cytochromes P450 3A4 and 2C9 and inhibits major hepatic glucuronosyltransferases.
        Drug Metab Dispos. 2004; 32: 587-594
        • Kosina P.
        • Maurel P.
        • Ulrichova J.
        • Dvorak Z.
        Effect of silybin and its glycosides on the expression of cytochromes P450 1A2 and 3A4 in primary cultures of human hepatocytes.
        J Biochem Mol Toxicol. 2005; 19: 149-153
        • Budzinski J.W.
        • Trudeau V.L.
        • Drouin C.E.
        • Panahi M.
        • Arnason J.T.
        • Foster B.C.
        Modulation of human cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) in Caco-2 cell monolayers by selected commercial-source milk thistle and goldenseal products.
        Can J Physiol Pharmacol. 2007; 85: 966-978
        • Gurley B.J.
        • Gardner S.F.
        • Hubbard M.A.
        • Williams D.K.
        • Gentry W.B.
        • Carrier J.
        • et al.
        In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes: Citrus aurantium, Echinacea purpurea, milk thistle, and saw palmetto.
        Clin Pharmacol Ther. 2004; 76: 428-440
        • Gurley B.
        • Hubbard M.A.
        • Williams D.K.
        • Thaden J.
        • Tong Y.
        • Gentry W.B.
        • et al.
        Assessing the clinical significance of botanical supplementation on human cytochrome P450 3A activity: comparison of a milk thistle and black cohosh product to rifampin and clarithromycin.
        J Clin Pharmacol. 2006; 46: 201-213
        • Ghosh A.
        • Biswas S.
        • Ghosh T.
        Preparation and evaluation of silymarin beta-cyclodextrin molecular inclusion complexes.
        J Young Pharm. 2011; 3: 205-210
        • Javed S.
        • Kohli K.
        • Ali M.
        Reassessing bioavailability of silymarin.
        Altern Med Rev. 2011; 16: 239-249
        • Foster B.C.
        • Foster M.S.
        • Vandenhoek S.
        • Krantis A.
        • Budzinski J.W.
        • Arnason J.T.
        • et al.
        An in vitro evaluation of human cytochrome P450 3A4 and P-glycoprotein inhibition by garlic.
        J Pharm Pharmacol. 2001; 4: 176-184
        • Zou L.
        • Harkey M.R.
        • Henderson G.L.
        Effects of herbal components on cDNA-expressed cytochrome P450 enzyme catalytic activity.
        Life Sci. 2002; 71: 1579-1589
        • Lawson L.D.
        • Gardner C.D.
        Composition, stability, and bioavailability of garlic products used in a clinical trial.
        J Agric Food Chem. 2005; 53: 6254-6261
        • Engdal S.
        • Nilsen O.G.
        In vitro inhibition of CYP3A4 by herbal remedies frequently used by cancer patients.
        Phytother Res. 2009; 23: 906-912
        • Ho B.E.
        • Shen D.D.
        • McCune J.S.
        • Bui T.
        • Risler L.
        • Yang Z.
        • et al.
        Effects of garlic on cytochromes P450 2C9- and 3A4-mediated drug metabolism in human hepatocytes.
        Sci Pharm. 2010; 78: 473-481
        • Raucy J.L.
        Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products.
        Drug Metab Dispos. 2003; 31: 533-539
        • Lawson L.D.
        • Wang Z.J.
        Low allicin release from garlic supplements: a major problem due to the sensitivities of alliinase activity.
        J Agric Food Chem. 2001; 49: 2592-2599
        • Cox M.C.
        • Low J.
        • Lee J.
        • Walshe J.
        • Denduluri N.
        • Berman A.
        • et al.
        Influence of garlic (Allium sativum) on the pharmacokinetics of docetaxel.
        Clin Cancer Res. 2006; 12: 4636-4640
        • Marre F.
        • Sanderink G.J.
        • de Sousa G.
        • Gaillard C.
        • Martinet M.
        • Rahmani R.
        Hepatic biotransformation of docetaxel (Taxotere) in vitro: involvement of the CYP3A subfamily in humans.
        Cancer Res. 1996; 56: 1296-1302
        • Hao M.
        • Zhao Y.
        • Chen P.
        • Huang H.
        • Liu H.
        • Jiang H.
        • et al.
        Structure-activity relationship and substrate-dependent phenomena in effects of ginsenosides on activities of drug-metabolizing P450 enzymes.
        PloS One. 2008; 3: e2697
        • Liu Y.
        • Ma H.
        • Zhang J.W.
        • Deng M.C.
        • Yang L.
        Influence of ginsenoside Rh1 and F1 on human cytochrome p450 enzymes.
        Planta Med. 2006; 72: 126-131
        • Izzo A.A.
        • Ernst E.
        Interactions between herbal medicines and prescribed drugs: an updated systematic review.
        Drugs. 2009; 69: 1777-1798
        • Liu Y.
        • Zhang J.W.
        • Li W.
        • Ma H.
        • Sun J.
        • Deng M.C.
        • et al.
        Ginsenoside metabolites, rather than naturally occurring ginsenosides, lead to inhibition of human cytochrome P450 enzymes.
        Toxicol Sci. 2006; 91: 356-364
        • He N.
        • Edeki T.
        The inhibitory effects of herbal components on CYP2C9 and CYP3A4 catalytic activities in human liver microsomes.
        Am J Ther. 2004; 11: 206-212
        • Malati C.Y.
        • Robertson S.M.
        • Hunt J.D.
        • Chairez C.
        • Alfaro R.M.
        • Kovacs J.A.
        • et al.
        Influence of Panax ginseng on cytochrome P450 (CYP)3A and P-glycoprotein (P-gp) activity in healthy participants.
        J Clin Pharmacol. 2012; 52: 932-939
        • Penzak S.R.
        • Busse K.H.
        • Robertson S.M.
        • Formentini E.
        • Alfaro R.M.
        • Davey Jr., R.T.
        Limitations of using a single postdose midazolam concentration to predict CYP3A-mediated drug interactions.
        J Clin Pharmacol. 2008; 48: 671-680
        • Bilgi N.
        • Bell K.
        • Ananthakrishnan A.N.
        • Atallah E.
        Imatinib and Panax ginseng: a potential interaction resulting in liver toxicity.
        Ann Pharmacother. 2010; 44: 926-928
      6. The Coca-Cola Company. Product descriptions: full throttle. <http://www.virtualvender.coca-cola.com/ft/index.jsp?brand_id=700/>; 2012 [accessed 25.06.2012].

        • Winslow L.C.
        • Kroll D.J.
        Herbs as medicines.
        Arch Intern Med. 1998; 158: 2192-2199
        • Harkey M.R.
        • Henderson G.L.
        • Gershwin M.E.
        • Stern J.S.
        • Hackman R.M.
        Variability in commercial ginseng products: an analysis of 25 preparations.
        Am J Clin Nutr. 2001; 73: 1101-1106
        • Schulz H.U.
        • Schurer M.
        • Krumbiegel G.
        • Wachter W.
        • Weyhenmeyer R.
        • Seidel G.
        The solubility and bioequivalence of silymarin preparations.
        Arzneimittelforschung. 1995; 45: 61-64
        • Imai H.
        • Kotegawa T.
        • Tsutsumi K.
        • Morimoto T.
        • Eshima N.
        • Nakano S.
        • et al.
        The recovery time-course of CYP3A after induction by St John’s wort administration.
        Br J Clin Pharmacol. 2008; 65: 701-707