Abstract
Objectives
Elderly patients are more likely to ingest prescription medications concurrently with botanical supplements, and may therefore be vulnerable to herb-drug interactions. Phytochemical-mediated modulation of cytochrome P450 (CYP) activity may underlie many herb-drug interactions. Some evidence suggests that CYP activity may decrease in the elderly. If so, herb-mediated changes in CYP activity may take on greater clinical relevance in this population. In this study, single timepoint, phenotypic metabolic ratios were used to determine whether long-term supplementation of St John’s wort, garlic oil, Panax ginseng, and Ginkgo biloba affected CYP1A2, CYP2D6, CYP2E1 or CYP3A4 activity in elderly subjects.
Methods
Twelve healthy volunteers between the ages of 60 and 76 years (mean age 67 years) were randomly assigned to receive each botanical supplement for 28 days followed by a 30-day washout period. Probe drug cocktails of midazolam, caffeine, chlorzoxazone and debrisoquine were administered before and at the end of supplementation. Pre- and post-supplementation phenotypic ratios were determined for CYP3A4, CYP1A2, CYP2E1 and CYP2D6 using 1-hydroxymidazolam/midazolam serum ratios (1-hour), paraxanthine/caffeine serum ratios (6-hour), 6-hydroxychlorzoxazone/chlorzoxazone serum ratios (2-hour) and debrisoquine urinary recovery ratios (8-hour), respectively. The content of purported ‘active’ phytochemicals was determined for each supplement.
Results
Comparisons of pre- and post-St John’s wort phenotypic ratios revealed significant induction of CYP3A4 (≈140%) and CYP2E1 activity (≈28%). Garlic oil inhibited CYP2E1 activity by approximately 22%. P. ginseng inhibition of CYP2D6 was statistically significant, but the magnitude of the effect (≈7%) did not appear to be clinically relevant. None of the supplements tested in this study appeared to affect CYP1A2 activity.
Conclusions
Elderly subjects, like their younger counterparts, are susceptible to herb-mediated changes in CYP activity, especially those involving St John’s wort. Pharmacokinetic herb-drug interactions stemming from alterations in CYP activity may adversely affect drug efficacy and/or toxicity. When compared with earlier studies that employed young subjects, the data suggest that some age-related changes in CYP responsivity to botanical supplementation may exist. Concomitant ingestion of botanical supplements with prescription medications, therefore, should be strongly discouraged in the elderly.
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Notes
The use of trade names is for product identification purposes only and does not imply endorsement.
References
Eisenberg DM, Davis 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: 1569–75
Klepser TB, Doucette WR, Horton MR, et al. Assessment of patient’s perceptions and beliefs regarding herbal therapies. Pharmacotherapy 2000; 20: 83–7
Kaufman DW, Kelly JP, Rosenberg L, et al. Recent patterns of medication use in the ambulatory adult population of the United States. JAMA 2002; 287: 337–44
Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs: a systematic review. Drugs 2001; 61: 2163–75
Ang-Lee MK, Moss J, Yuan C. Herbal medicines and perioperative care. JAMA 2001; 286: 208–16
Brazier NC, Levine MAH. Drug-herb interaction among commonly used conventional medicines: a compendium for health care professionals. Am J Ther 2003; 10: 163–9
Gurley BJ, Hagan DW. Herbal and dietary supplement interactions with drugs. In: McCabe BJ, Frankel EH, Wolfe JJ, editors. Handbook of food-drug interactions. Boca Raton: CRC Press, 2003: 259–293
Nelson L, Perrone J. Herbal and alternative medicine. Emerg Med Clin North Am 2000; 18: 709–22
Gunther S, Patterson RE, Kristal AR, et al. Demographic and health-related correlates of herbal and specialty supplement use. J Am Diet Assoc 2004; 104: 27–34
Skinner CM, Rangasami J. Preoperative use of herbal medicines: a patient survey. Br J Anaesth 2002; 89: 792–5
Rhee SM, Garg VK, Hershey CO. Use of complementary and alternative medicines by ambulatory patients. Arch Intern Med 2004; 164: 1004–9
Adusumilli PS, Ben-Porat L, Pereira M, et al. The prevalence and predictors of herbal medicine use in surgical patients. J Am Coll Surg 2004; 198: 583–90
Foster DF, Phillips RS, Hamel B. Alternative medicine use in older Americans. J Am Geriatr Soc 2000; 48: 1560–5
Cohen RJ, Ek K, Pan CX. Complementary and alternative medicine (CAM) use by older adults: a comparison of self-report and physician chart documentation. J Gerontol 2002; 57A: M223–7
Dergal JM, Gold JL, Laxer DA, et al. Potential interactions between herbal medicines and conventional drug therapies used by older adults attending a memory clinic. Drugs Aging 2002; 19: 879–86
Wang Z, Gorski JC, Hamman MA, et al. The effects of St John’s wort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther 2001; 70: 317–26
Gurley BJ, Gardner SF, Hubbard MA, et al. Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans. Clin Pharmacol Ther 2002; 72: 276–82
Markowitz JS, Donovan JL, DeVane CL, et al. Multiple-dose administration of Ginkgo biloba did not affect cytochrome P-450 2D6 or 3A4 activity in normal volunteers. J Clin Psychopharmacol 2003; 23: 576–81
Markowitz JS, DeVane CL, Chavin KD, et al. Effects of garlic (Allium sativum L.) supplementation on cytochrome P450 2D6 and 3A4 activity in healthy volunteers. Clin Pharmacol Ther 2003; 74: 170–7
Anderson GD, Rosito G, Mohustsy MA, et al. Drug interaction potential of soy extract and Panax ginseng. J Clin Pharmacol 2003; 43: 643–8
Gorski JC, Huang S-M, Pinto A, et al. The effect of Echinacea (Echinacea purpurea root) on cytochrome P450 activity in vivo. Clin Pharmacol Ther 2004; 75: 89–100
Wentworth JM, Agostini M, Love J, et al. St John’s wort, a herbal antidepressant, activates the steroid X receptor. J Endocrinol 2000; 166: R11–6
Moore LB, Goodwin B, Jones SA, et al. St John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci U S A 2000; 97: 7500–2
Piscitelli SC, Burstein AH, Weiden N, et al. The effect of garlic supplements on the pharmacokinetics of saquinavir. Clin Infect Dis 2002; 34: 234–8
Gold PE, Cahill L, Wenk GL. The lowdown on Ginkgo biloba. Sci Am 2003 Apr; 288(4): 86–91
Kales HC, Blow FC, Welsh DE, et al. Herbal products and other supplements: use by elderly veterans with depression and dementia and their caregivers. J Geriatr Psychiatry Neurol 2004; 17: 25–31
Anderson GD, Rosito G, Mohustsy MA, et al. Drug interaction potential of soy extract and Panax ginseng. J Clin Pharmacol 2003; 43: 643–8
Kinirons MT, Crome P. Clinic pharmacokinetic considerations in the elderly. Clin Pharmacokinet 1997; 33: 302–12
Tanaka E. In vivo age-related changes in hepatic drug-oxidizing capacity in humans. J Clin Pharm Ther 1998; 23: 247–55
McLean AJ, Le Couteur DG. Aging biology and geriatric clinical pharmacology. Pharmacol Rev 2004; 56: 163–84
Fuhr U, Rost KL. Simple and reliable CYP1A2 phenotyping by the paraxanthine/caffeine ratio in plasma and in saliva. Pharmacogenetics 1994; 4: 109–16
Frye RF, Matzke GR, Adedoyin A, et al. Validation of the five-drug ‘Pittsburgh cocktail’ approach for assessment of selective regulation of drug-metabolizing enzymes. Clin Pharmacol Ther 1997; 62: 365–76
Streetman DS, Bertino JS, Nafziger AN. Phenotyping of drug metabolizing enzymes in adults: a review of in-vivo cytochrome P450 phenotyping probes. Pharmacogenetics 2000; 10: 187–216
Gurley BJ, Gardner SF, Hubbard MA, 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: 428–40
Palmer JL, Scott RJ, Gibson A, et al. An interaction between cytochrome P450 probe substrates chlorzoxazone (CYP2E1) and midazolam (CYP3A). Br J Clin Pharmacol 2001; 52: 555–61
Holland DT, Godfredsen KA, Page T, et al. Simple high performance liquid chromatography method for the simultaneous determination of serum caffeine and paraxanthine following rapid sample preparation. J Chromatogr B Biomed Sci Appl 1998; 707: 105–10
Frye RF, Stiff DD. Determination of chlorzoxazone and 6-hydroxychlorzoxazone in human plasma and urine by high-performance liquid chromatography. J Chromatogr B Biomed Appl 1996; 686: 291–6
Frye RF, Branch RA. Improved high-performance liquid Chromatographic determination of debrisoquine and 4-hydroxydebrisoquin in human urine following direct injection. J Chromatogr B Biomed Appl 1996; 677: 178–82
Sautou V, Chopineau J, Terrisse MP, et al. Solid-phase extraction of midazolam and two of its metabolites from plasma for high performance liquid Chromatographic analysis. J Chromatogr 1991; 571: 298–304
Liu FF, Ang CYW, Heinze TM, et al. Evaluation of major active components in St. John’s wort dietary supplements by high-performance liquid chromatography with photodiode array detection and electrospray mass spectrometric confirmation. J Chromatogr A 2000; 888: 85–92
Cui Y, Gurley B, Ang CYW, et al. Determination of hyperforin in human plasma using solid-phase extraction and high-performance liquid chromatography with ultraviolet detection. J Chromatogr B Analyt Technol Biomed Life Sci 2002; 780: 129–35
Lawson L, Wang Z, Hughes BG. Identification and HPLC quantitation of the Sulfides and dialk(en)yl thiosulfinates in commercial garlic products. Planta Med 1991; 57: 363–70
Li W, Fitzloff JF. Simultaneous determination of terpene lactones and flavonoid aglycones in Ginkgo biloba by high-performance liquid chromatography with evaporative light scattering detection. J Pharm Biomed Anal 2002; 30: 67–75
Zhu B, Ou-Yang DS, Cheng Z, et al. Single plasma sampling to predict oral clearance of CYP3A probe midazolam. Acta Pharmacol Sin 2001; 22: 634–8
Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. Mahwah (NJ): Lawrence Erlbaum Associates Publishers, 1988: 19–42
Gurley BJ, Gardner SF, Hubbard MA, et al. In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4 phenotypes. Clin Pharmacol Ther 2005. In press
De Los Reyes GC, Koda RT. Determining hyperforin and hypericin content in eight brands of St. John’s wort. Am J Health Syst Pharm 2002; 59: 545–7
Ganzera M, Zhao J, Khan IA. Hypericum perforatum: chemical profiling and quantitative results of St John’s wort products by an improved high-performance liquid chromatography method. J Pharm Sci 2002; 91: 623–30
Wurglics M, Westerhoff K, Kaunzinger A, et al. Batch-to-batch reproducibility of St John’s wort preparations. Pharmacopsychiatry 2001; 34Suppl. 1: S152–6
Hunt CM, Strater S, Stave GM. Effect of normal aging on the activity of human hepatic cytochrome P450IIE1. Biochem Pharmacol 1990; 40: 1666–9
Nakajima T, Wang RS. Induction of cytochrome P450 by toluene. Int J Biochem 1994; 26: 1333–40
Koop DR, Tierney DJ. Multiple mechanisms in the regulation of ethanol-inducible cytochrome P450IIE1. Bioessays 1990; 12: 429–35
Chien JY, Thummel KE, Slattery JT. Pharmacokinetic consequences of induction of CYP2E1 by ligand stabilization. Drug Metab Dispos 1997; 25: 1165–75
Kenna JG, Jones RM. The organ toxicity of inhaled anesthetics. Anesth Analg 1995; 81: S51–66
Loizou GD, Crocker J. The effects of alcohol and diallyl sulphide on CYP2E1 activity in humans: a phenotyping study using chlorzoxazone. Hum Exp Toxicol 2001; 20: 321–7
Haber D, Siess M, Canivenc-Lavier M, et al. Differential effects of dietary diallyl sulfide and diallyl disulfide on rat intestinal and hepatic drug-metabolizing enzymes. J Toxicol Environ Health 1995; 44: 423–34
Siess M, Le Bon A, Canivenc-Lavier M, et al. Modification of hepatic drug-metabolizing enzymes in rats treated with alkyl sulfides. Cancer Lett 1997; 120: 195–201
Yang CS, Chhabra SK, Hong J, et al. Mechanisms of inhibition of chemical toxicity and carcinogenesis by diallyl sulfide (DAS) and related compounds from garlic. J Nutr 2001; 131: 1041S–5S
Chung KF, Dent G, McCuster M, et al. Effect of ginkgolide mixture (BN 52063) in antagonizing skin and platelet responses to platelet activating factor in man. Lancet 1987; I: 248–51
Duche JC, Barre J, Guinot P, et al. Effect of Ginkgo biloba extract on microsomal enzyme induction. Int J Clin Pharm Res 1989; 9: 165–8
Janetzky K, Morreale AP. Probable interaction between warfarin and ginseng. Am J Health Syst Pharm 1997; 54: 692–3
Yuan C-S, Wei G, Dey L, et al. American ginseng reduces warfarin’s effect in healthy patients: a randomized controlled trial. Ann Intern Med 2004; 141: 23–7
Acknowledgements
Supported through grants from the NIH/NIA (RO3AG17733-01) and NIH/NCRR to the General Clinical Research Center of the University of Arkansas for Medical Sciences (M01RR14288).
The authors would like to acknowledge Dr Ikhlas Khan (University of Mississippi, National Center for Natural Products Research), and Dr Mark Roman and Brian Schaneberg (Chromadex, Inc., Clearwater, Florida) for analysis of supplements containing Panax ginseng, Ginkgo biloba and garlic oil.
The authors have no financial or other interests to disclose.
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Gurley, B.J., Gardner, S.F., Hubbard, M.A. et al. Clinical Assessment of Effects of Botanical Supplementation on Cytochrome P450 Phenotypes in the Elderly. Drugs Aging 22, 525–539 (2005). https://doi.org/10.2165/00002512-200522060-00006
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DOI: https://doi.org/10.2165/00002512-200522060-00006