Understanding and preventing drug-drug and drug-gene interactions

Cara Tannenbaum, Nancy L Sheehan, Cara Tannenbaum, Nancy L Sheehan

Abstract

Concomitant administration of multiple drugs can lead to unanticipated drug interactions and resultant adverse drug events with their associated costs. A more thorough understanding of the different cytochrome P450 isoenzymes and drug transporters has led to new methods to try to predict and prevent clinically relevant drug interactions. There is also an increased recognition of the need to identify the impact of pharmacogenetic polymorphisms on drug interactions. More stringent regulatory requirements have evolved for industry to classify cytochrome inhibitors and inducers, test the effect of drug interactions in the presence of polymorphic enzymes, and evaluate multiple potentially interacting drugs simultaneously. In clinical practice, drug alert software programs have been developed. This review discusses drug interaction mechanisms and strategies for screening and minimizing exposure to drug interactions. We also provide future perspectives for reducing the risk of clinically significant drug interactions.

Keywords: cytochrome-mediated drug interactions; drug transporters; drug-drug-gene interactions; pharmacogenomics; polypharmacy.

References

    1. Huang SM, Strong JM, Zhang L. New era in drug interaction evaluation: US FDA update on CYP enzymes, transporters, and the guidance process. J Clin Pharmacol. 2008;48(6):662–70.

    2. This study provides a succinct account of the historical events leading to the recognition that drugs that share the same CYP450 metabolic pathways could interact and cause serious adverse events. Also highlights the most recent requirements for industry to characterize potential CYP450 drug–drug interactions during the drug preapproval process.

    1. Monahan BP, Ferguson CL, Killeavy ES. Torsades de pointes occurring in association with terfenadine use. JAMA. 1990;264(21):2788–90.
    1. US FDA Guidance for Industry: drug metabolism/drug interactions in the drug development process: studies in vitro. 1997 Available from: [Last accessed 21 February 2013]
    1. US FDA Guidance for Industry: in vivo metabolism/drug interaction: study design, data analysis and recommendation for dosing and labeling. 1999 Available from: [Last accessed 21 February 2013]
    1. Huang SM, Temple R, Throckmorton DC, Lesko LJ. Drug interaction studies: study design, data analysis, and implications for dosing and labeling. Clin Pharmacol Ther. 2007;81(2):298–304.
    1. Glintborg B, Andersen SE, Dalhoff K. Drug-drug interactions among recently hospitalised patients--frequent but mostly clinically insignificant. Eur J Clin Pharmacol. 2005;61(9):675–81.
    1. Doucet J, Chassagne P, Trivalle C. Drug-drug interactions related to hospital admissions in older adults: a prospective study of 1000 patients. J Am Geriatr Soc. 1996;44(8):944–8.
    1. Malone DC, Hutchins DS, Haupert H. Assessment of potential drug-drug interactions with a prescription claims database. Am J Health Syst Pharm. 2005;62(19):1983–91.
    1. Hines LE, Malone DC, Murphy JE. Recommendations for generating, evaluating, and implementing drug-drug interaction evidence. Pharmacotherapy. 2012;32(4):304–13.
    1. Zakrzewski-Jakubiak H, Doan J, Lamoureux P. Detection and prevention of drug-drug interactions in the hospitalized elderly: utility of new cytochrome P450-based software. Am J Geriatr Pharmacother. 2011;9(6):461–70.

    2. This original study describes a new multidrug cytochrome-specific drug interaction software and provides consensus recommendations emitted by a panel of geriatric pharmacists for the management of different cytochrome-mediated drug interaction scenarios, based on the different cytochrome binding affinities of the object and precipitating drugs.

    1. Lapane KL, Waring ME, Schneider KL. A mixed method study of the merits of e-prescribing drug alerts in primary care. J Gen Intern Med. 2008;23(4):442–6.
    1. Magnus D, Rodgers S, Avery AJ. GPs’ views on computerized drug interaction alerts: questionnaire survey. J Clin Pharm Ther. 2002;27(5):377–82.
    1. Monane M, Matthias DM, Nagle BA, Kelly MA. Improving prescribing patterns for the elderly through an online drug utilization review intervention: a system linking the physician, pharmacist, and computer. JAMA. 1998;280(14):1249–52.
    1. Shapiro LE, Shear NH. Drug interactions: proteins, pumps, and P-450s. J Am Acad Dermatol. 2002;47(4):467–84. quiz 485-8.

    2. An excellent clinical review of the mechanisms behind common drug interactions due to environmental, genetic, nutritional and pharmacokinetic factors.

    1. Endres CJ, Hsiao P, Chung FS, Unadkat JD. The role of transporters in drug interactions. Eur J Pharm Sci. 2006;27(5):501–17.
    1. Kis O, Robillard K, Chan GN, Bendayan R. The complexities of antiretroviral drug-drug interactions: role of ABC and SLC transporters. Trends Pharmacol Sci. 2010;31(1):22–35.
    1. Klaassen CD, Aleksunes LM. Xenobiotic, bile acid, and cholesterol transporters: function and regulation. Pharmacol Rev. 2010;62(1):1–96.
    1. Pedersen JM, Matsson P, Bergstrom CA. Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11) Toxicol Sci. 2013;136(2):328–43.
    1. Shorr RI, Ray WA, Daugherty JR, Griffin MR. Concurrent use of nonsteroidal anti-inflammatory drugs and oral anticoagulants places elderly persons at high risk for hemorrhagic peptic ulcer disease. Arch Intern Med. 1993;153(14):1665–70.
    1. Lehto P, Kivisto KT, Neuvonen PJ. The effect of ferrous sulphate on the absorption of norfloxacin, ciprofloxacin and ofloxacin. Br J Clin Pharmacol. 1994;37(1):82–5.
    1. Zhu L, Persson A, Mahnke L. Effect of low-dose omeprazole (20 mg daily) on the pharmacokinetics of multiple-dose atazanavir with ritonavir in healthy subjects. J Clin Pharmacol. 2011;51(3):368–77.
    1. Kolars JC, Lown KS, Schmiedlin-Ren P. CYP3A gene expression in human gut epithelium. Pharmacogenetics. 1994;4(5):247–59.
    1. Wu CY, Benet LZ, Hebert MF. Differentiation of absorption and first-pass gut and hepatic metabolism in humans: studies with cyclosporine. Clin Pharmacol Ther. 1995;58(5):492–7.
    1. Simonson SG, Raza A, Martin PD. Rosuvastatin pharmacokinetics in heart transplant recipients administered an antirejection regimen including cyclosporine. Clin Pharmacol Ther. 2004;76(2):167–77.
    1. van Heeswijk R, Verboven P, Vandevoorde A. Pharmacokinetic interaction between telaprevir and methadone. Antimicrob Agents Chemother. 2013;57(5):2304–9.
    1. Clarke SE, Jones BC. Human cytochromes P450 and their role in metabolism-based drug-drugs interactions. In: Rodrigues AD, editor. Drug-drug interaction. Inform Healthcare; NY, USA: 2008. pp. 53–85. editor. p.
    1. Hines LE, Murphy JE. Potentially harmful drug-drug interactions in the elderly: a review. Am J Geriatr Pharmacother. 2011;9(6):364–77.

    2. An informative review of the evidence for common cytochrome-mediated and noncytochrome-mediated drug interactions leading to hospitalization in the elderly.

    1. Kiang TK, Ensom MH, Chang TK. UDP-glucuronosyltransferases and clinical drug-drug interactions. Pharmacol Ther. 2005;106(1):97–132.
    1. Lertora JJ, Rege AB, Greenspan DL. Pharmacokinetic interaction between zidovudine and valproic acid in patients infected with human immunodeficiency virus. Clin Pharmacol Ther. 1994;56(3):272–8.
    1. Antoniou T, Gough K, Yoong D, Arbess G. Severe anemia secondary to a probable drug interaction between zidovudine and valproic acid. Clin Infect Dis. 2004;38(5):e38–40.
    1. Rowland A, Elliot DJ, Williams JA. In vitro characterization of lamotrigine N2-glucuronidation and the lamotrigine-valproic acid interaction. Drug Metab Dispos. 2006;34(6):1055–62.
    1. Morris RG, Black AB, Lam E, Westley IS. Clinical study of lamotrigine and valproic acid in patients with epilepsy: using a drug interaction to advantage? Ther Drug Monit. 2000;22(6):656–60.
    1. Huang CW, Tsai JJ, Lai ML. Lamotrigine-related skin rashes in adults. Kaohsiung J Med Sci. 2002;18(11):566–72.
    1. Ebert U, Thong NQ, Oertel R, Kirch W. Effects of rifampicin and cimetidine on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects. Eur J Clin Pharmacol. 2000;56(4):299–304.
    1. Gallicano KD, Sahai J, Shukla VK. Induction of zidovudine glucuronidation and amination pathways by rifampicin in HIV-infected patients. Br J Clin Pharmacol. 1999;48(2):168–79.
    1. Wakasugi H, Yano I, Ito T. Effect of clarithromycin on renal excretion of digoxin: interaction with P-glycoprotein. Clin Pharmacol Ther. 1998;64(1):123–8.
    1. Kyrklund C, Backman JT, Neuvonen M, Neuvonen PJ. Gemfibrozil increases plasma pravastatin concentrations and reduces pravastatin renal clearance. Clin Pharmacol Ther. 2003;73(6):538–44.
    1. Wiklund O, Angelin B, Bergman M. Pravastatin and gemfibrozil alone and in combination for the treatment of hypercholesterolemia. Am J Med. 1993;94(1):13–20.
    1. Nakagomi-Hagihara R, Nakai D, Tokui T. Inhibition of human organic anion transporter 3 mediated pravastatin transport by gemfibrozil and the metabolites in humans. Xenobiotica. 2007;37(4):416–26.
    1. Seripa D, Pilotto A, Panza F. Pharmacogenetics of cytochrome P450 (CYP) in the elderly. Ageing Res Rev. 2010;9(4):457–74.
    1. Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part II. Clin Pharmacokinet. 2009;48(12):761–804.
    1. Sim SC, Kacevska M, Ingelman-Sundberg M. Pharmacogenomics of drug-metabolizing enzymes: a recent update on clinical implications and endogenous effects. Pharmacogenomics J. 2013;13(1):1–11.

    2. Outstanding summary of the quality of evidence available to establish the major effects of cytochrome polymorphism on the outcome of common exogenous drug and nondrug exposures.

    1. Zanger UM, Turpeinen M, Klein K, Schwab M. Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal Bioanal Chem. 2008;392(6):1093–108.
    1. Holmes MV, Perel P, Shah T. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and meta-analysis. JAMA. 2011;306(24):2704–14.
    1. Schroth W, Goetz MP, Hamann U. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA. 2009;302(13):1429–36.
    1. Crews KR, Gaedigk A, Dunnenberger HM. Clinical pharmacogenetics implementation consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014. Clin Pharmacol Ther. 2014;95(4):376–82.
    1. Kelly CM, Juurlink DN, Gomes T. Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. BMJ. 2010;340:c693.
    1. Ehmer U, Kalthoff S, Fakundiny B. Gilbert syndrome redefined: a complex genetic haplotype influences the regulation of glucuronidation. Hepatology. 2012;55(6):1912–21.
    1. Lankisch TO, Moebius U, Wehmeier M. Gilbert’s disease and atazanavir: from phenotype to UDP-glucuronosyltransferase haplotype. Hepatology. 2006;44(5):1324–32.
    1. Innocenti F, Undevia SD, Iyer L. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol. 2004;22(8):1382–8.
    1. Lankisch TO, Schulz C, Zwingers T. Gilbert’s Syndrome and irinotecan toxicity: combination with UDP-glucuronosyltransferase 1A7 variants increases risk. Cancer Epidemiol Biomarkers Prev. 2008;17(3):695–701.
    1. Izzedine H, Hulot JS, Villard E. Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy. J Infect Dis. 2006;194(11):1481–91.
    1. Hyland R, Jones BC, Smith DA. Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole. Drug Metab Dispos. 2003;31(5):540–7.
    1. Mikus G, Scholz IM, Weiss J. Pharmacogenomics of the triazole antifungal agent voriconazole. Pharmacogenomics. 2011;12(6):861–72.
    1. Zhu L, Uy J, Brüggemann R. CYP2C19 genotype-dependent pharmacokinetic drug interaction between voriconazole and ritonavir boosted atazanavir in healthy subjects; abstract O_08; 16–18 April 2012; Barcelona, Spain. 13th International Workshop on Clinical Pharmacology of HIV Therapy.
    1. Preskorn SH, Kane CP, Lobello K. Cytochrome P450 2D6 phenoconversion is common in patients being treated for depression: implications for personalized medicine. J Clin Psychiatry. 2013;74(6):614–21.
    1. Fischer HD, Juurlink DN, Mamdani MM. Hemorrhage during warfarin therapy associated with cotrimoxazole and other urinary tract anti-infective agents: a population-based study. Arch Intern Med. 2010;170(7):617–21.
    1. Schelleman H, Bilker WB, Brensinger CM. Warfarin with fluoroquinolones, sulfonamides, or azole antifungals: interactions and the risk of hospitalization for gastrointestinal bleeding. Clin Pharmacol Ther. 2008;84(5):581–8.
    1. Antoniou T, Gomes T, Mamdani MM, Juurlink DN. Trimethoprim/sulfamethoxazole-induced phenytoin toxicity in the elderly: a population-based study. Br J Clin Pharmacol. 2011;71(4):544–9.
    1. Juurlink DN, Mamdani M, Kopp A. Drug-drug interactions among elderly patients hospitalized for drug toxicity. JAMA. 2003;289(13):1652–8.
    1. Schelleman H, Bilker WB, Brensinger CM. Anti-infectives and the risk of severe hypoglycemia in users of glipizide or glyburide. Clin Pharmacol Ther. 2010;88(2):214–22.
    1. Wright AJ, Gomes T, Mamdani MM. The risk of hypotension following co-prescription of macrolide antibiotics and calcium-channel blockers. CMAJ. 2011;183(3):303–7.
    1. Chang JT, Staffa JA, Parks M, Green L. Rhabdomyolysis with HMG-CoA reductase inhibitors and gemfibrozil combination therapy. Pharmacoepidemiol Drug Saf. 2004;13(7):417–26.
    1. US FDA USA Department of Health and Human Services. Guidance for Industry. Drug Interaction Studies - Study design, data analysis, implications for dosing, and labeling recommendations. Drafts Guidance. 2012 Available from: [Last accessed 5 August 2013]
    1. Johnell K, Klarin I. The relationship between number of drugs and potential drug-drug interactions in the elderly: a study of over 600,000 elderly patients from the Swedish Prescribed Drug Register. Drug Saf. 2007;30(10):911–18.
    1. Doan J, Zakrzewski-Jakubiak H, Roy J. Prevalence and risk of potential cytochrome P450-mediated drug-drug interactions in older hospitalized patients with polypharmacy. Ann Pharmacother. 2013;47(3):324–32.
    1. Davies SJ, Eayrs S, Pratt P, Lennard MS. Potential for drug interactions involving cytochromes P450 2D6 and 3A4 on general adult psychiatric and functional elderly psychiatric wards. Br J Clin Pharmacol. 2004;57(4):464–72.
    1. Mulder H, Heerdink ER, van Iersel EE. Prevalence of patients using drugs metabolized by cytochrome P450 2D6 in different populations: a cross-sectional study. Ann Pharmacother. 2007;41(3):408–13.
    1. Mann HJ. Drug-associated disease: cytochrome P450 interactions. Crit Care Clin. 2006;22(2):329–45.

    2. This review highlights the shortcomings of regulatory measures and consensus references to reduce the risk of clinically important cytochrome-mediated drug–drug interactions. The author lists suggestions for minimizing the risk of severe cytochrome-mediated drug interactions in acutely ill patients.

    1. Malone DC, Abarca J, Hansten PD. Identification of serious drug-drug interactions: results of the partnership to prevent drug-drug interactions. J Am Pharm Assoc. 2003;2004;44(2):142–51.
    1. Andersson ML, Lindh JD, Mannheimer B. The impact of interacting drugs on dispensed doses of warfarin in the Swedish population: a novel use of population based drug registers. J Clin Pharmacol. 2013;53(12):1322–7.
    1. Andersson ML, Bottiger Y, Lindh JD. Impact of the drug-drug interaction database SFINX on prevalence of potentially serious drug-drug interactions in primary health care. Eur J Clin Pharmacol. 2013;69(3):565–71.
    1. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. E7 Studies in support of special populations: geriatrics Questions and Answers. 2012. Available from: [Last accessed 2 March 2013]
    1. Anthony M, Romero K, Malone DC. Warfarin interactions with substances listed in drug information compendia and in the FDA-approved label for warfarin sodium. Clin Pharmacol Ther. 2009;86(4)):425–9.
    1. Boyce RD, Collins C, Clayton M. Inhibitory metabolic drug interactions with newer psychotropic drugs: inclusion in package inserts and influences of concurrence in drug interaction screening software. Ann Pharmacother. 2012;46(10):1287–98.
    1. Boyce RD, Handler SM, Karp JF, Hanlon JT. Age-related changes in antidepressant pharmacokinetics and potential drug-drug interactions: a comparison of evidence-based literature and package insert information. Am J Geriatr Pharmacother. 2012;10(2):139–50.
    1. DiNicolantonio JJ, Serebruany VL. Challenging the FDA black box warning for high aspirin dose with ticagrelor in patients with diabetes. Diabetes. 2013;62(3):669–71.
    1. Ridgely MS, Greenberg MD. Too many alerts, too much liability: sorting through the malpractice implications of drug-drug interaction clinical decision support. St Louis U J Health L & Pol’y. 2012;5(2):257–96.
    1. Marroum PJ, Uppoor RS, Parmelee T. In vivo drug-drug interaction studies--a survey of all new molecular entities approved from 1987. Clin Pharmacol Ther. 2000;68(3):280–5.
    1. Yoshida N, Yamada A, Mimura Y. Trends in new drug interactions for pharmaceutical products in Japan. Pharmacoepidemiol. Drug Saf. 2006;15(6):421–7.
    1. D’Andrea G, D’Ambrosio RL, Di Perna P. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood. 2005;105(2):645–9.
    1. Gage BF, Eby C, Johnson JA. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther. 2008;84(3):326–31.
    1. Gong IY, Tirona RG, Schwarz UI. Prospective evaluation of a pharmacogenetics-guided warfarin loading and maintenance dose regimen for initiation of therapy. Blood. 2011;118(11):3163–71.
    1. Anderson JL, Horne BD, Stevens SM. A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II) Circulation. 2012;125(16):1997–2005.
    1. Johnson JA, Gong L, Whirl-Carrillo M. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther. 2011;90(4):625–9.
    1. de Denus S, Letarte N, Hurlimann T. An evaluation of pharmacists’ expectations towards pharmacogenomics. Pharmacogenomics. 2013;14(2):165–75.
    1. Mills R, Voora D, Peyser B, Haga SB. Delivering pharmacogenetic testing in a primary care setting. Pharmgenomics Pers Med. 2013;6:105–12.
    1. Abarca J, Colon LR, Wang VS. Evaluation of the performance of drug-drug interaction screening software in community and hospital pharmacies. J Manag Care Pharm. 2006;12(5):383–9.
    1. Sweidan M, Reeve JF, Brien JA. Quality of drug interaction alerts in prescribing and dispensing software. Med J Aust. 2009;190(5):251–4.
    1. Saverno KR, Hines LE, Warholak TL. Ability of pharmacy clinical decision-support software to alert users about clinically important drug-drug interactions. J Am Med Inform Assoc. 2011;18(1):32–7.
    1. Smithburger PL, Buckley MS, Bejian S. A critical evaluation of clinical decision support for the detection of drug-drug interactions. Expert Opin Drug Saf. 2011;10(6):871–82.

    2. This review study critically appraises the shortcomings of drug alert software and provides suggestions for future improvement.

    1. Riedmann D, Jung M, Hackl WO. Development of a context model to prioritize drug safety alerts in CPOE systems. BMC Med Inform Decis Mak. 2011;11:35.
    1. Duke JD, Bolchini D. A successful model and visual design for creating context-aware drug-drug interaction alerts. AMIA Annu Symp Proc. 2011;2011:339–48.
    1. Intermed-Rx application. Available from:
    1. Sheehan NL, Kelly DV, Tseng AL. Evaluation of HIV drug interaction web sites. Ann Pharmacother. 2003;37(11):1577–86.
    1. Tamblyn R, Huang A, Taylor L. A randomized trial of the effectiveness of on-demand versus computer-triggered drug decision support in primary care. J Am Med Inform Assoc. 2008;15(4):430–8.
    1. Floor-Schreudering A, Geerts AF, Aronson JK. Checklist for standardized reporting of drug-drug interaction management guidelines. Eur J Clin Pharmacol. 2014;70(3):313–18.
    1. Antoniou T, Gomes T, Mamdani MM, Juurlink DN. Ciprofloxacin-induced theophylline. toxicity: a population-based study. Eur J Clin Pharmacol. 2011;67(5):521–6.
    1. Niemi M, Backman JT, Neuvonen M, Neuvonen PJ. Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide. Diabetologia. 2003;46(3):347–51.
    1. LeBel M, Masson E, Guilbert E. Effects of rifabutin and rifampicin on the pharmacokinetics of ethinylestradiol and norethindrone. J Clin Pharmacol. 1998;38(11):1042–50.
    1. Skolnick JL, Stoler BS, Katz DB, Anderson WH. Rifampin, oral contraceptives, and pregnancy. JAMA. 1976;236(12):1382.
    1. Patel AM, Shariff S, Bailey DG. Statin toxicity from macrolide antibiotic coprescription: a population-based cohort study. Ann Intern Med. 2013;158(12):869–76.
    1. Schwarze-Zander C, Klingmuller D, Klumper J. Triamcinolone and ritonavir leading to drug-induced Cushing syndrome and adrenal suppression: description of a new case and review of the literature. Infection. 2013;41(6):1183–7.

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