Skip to main content
SpringerLink
Log in

Complex Drug–Drug–Gene–Disease Interactions Involving Cytochromes P450: Systematic Review of Published Case Reports and Clinical Perspectives

  • Systematic Review
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Drug pharmacokinetics (PK) is influenced by multiple intrinsic and extrinsic factors, among which concomitant medications are responsible for drug–drug interactions (DDIs) that may have a clinical relevance, resulting in adverse drug reactions or reduced efficacy. The addition of intrinsic factors affecting cytochromes P450 (CYPs) activity and/or expression, such as genetic polymorphisms and diseases, may potentiate the impact and clinical relevance of DDIs. In addition, greater variability in drug levels and exposures has been observed when such intrinsic factors are present in addition to concomitant medications perpetrating DDIs. This variability results in poor predictability of DDIs and potentially dramatic clinical consequences. The present review illustrates the issue of complex DDIs using systematically searched published case reports of DDIs involving genetic polymorphisms, renal impairment, cirrhosis, and/or inflammation. Current knowledge on the impact of each of these factors on drug exposure and DDIs is summarized and future perspectives for the management of such complex DDIs in clinical practice are discussed, including the use of advanced Computerized Physician Order Entry (CPOE) systems, the development of model-based dose optimization strategies, and the education of healthcare professionals with respect to personalized medicine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Miguel A, Azevedo LF, Araujo M, et al. Frequency of adverse drug reactions in hospitalized patients: a systematic review and meta-analysis. Pharmacoepidemiol Drug Saf. 2012;21(11):1139–54.

    Article  PubMed  Google Scholar 

  2. Marengoni A, Pasina L, Concoreggi C, et al. Understanding adverse drug reactions in older adults through drug-drug interactions. Eur J Intern Med. 2014;25(9):843–6.

    Article  PubMed  CAS  Google Scholar 

  3. Pirmohamed M, James S, Meakin S, et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ. 2004;329(7456):15–9.

    Article  PubMed  PubMed Central  Google Scholar 

  4. McDonnell PJ, Jacobs MR. Hospital admissions resulting from preventable adverse drug reactions. Ann Pharmacother. 2002;36(9):1331–6.

    Article  PubMed  Google Scholar 

  5. Goldberg RM, Mabee J, Chan L, et al. Drug-drug and drug-disease interactions in the ED: analysis of a high-risk population. Am J Emerg Med. 1996;14(5):447–50.

    Article  PubMed  CAS  Google Scholar 

  6. Hohl CM, Dankoff J, Colacone A, et al. Polypharmacy, adverse drug-related events, and potential adverse drug interactions in elderly patients presenting to an emergency department. Ann Emerg Med. 2001;38(6):666–71.

    Article  PubMed  CAS  Google Scholar 

  7. Lexi-Interact (database). 2017. Available at: www.lexi.com/. Accessed 23 Aug 2017.

  8. Multicheck Drug Interaction Checker (database) 2017. http://online.epocrates.com/noFrame/. Accessed 23 Aug 2017.

  9. Thériaque (database). 2017. www.theriaque.org/apps/recherche/rch_simple.php. Accessed 23 Aug 2017.

  10. Marsousi N, Samer CF, Fontana P, et al. Coadministration of ticagrelor and ritonavir: toward prospective dose adjustment to maintain an optimal platelet inhibition using the PBPK approach. Clin Pharmacol Ther. 2016;100(3):295–304.

    Article  PubMed  CAS  Google Scholar 

  11. Moher D, Pham B, Klassen TP, et al. What contributions do languages other than English make on the results of meta-analyses? J Clin Epidemiol. 2000;53(9):964–72.

    Article  PubMed  CAS  Google Scholar 

  12. Bouatou Y, Samer CF, Ing Lorenzini KR, et al. Therapeutic drug monitoring of voriconazole: a case report of multiple drug interactions in a patient with an increased CYP2C19 activity. AIDS Res Ther. 2014;11:25.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Ozdemir V, Kalow W, Okey AB, et al. Treatment-resistance to clozapine in association with ultrarapid CYP1A2 activity and the C– > A polymorphism in intron 1 of the CYP1A2 gene: effect of grapefruit juice and low-dose fluvoxamine. J Clin Psychopharmacol. 2001;21(6):603–7.

    Article  PubMed  CAS  Google Scholar 

  14. Shah RR, Smith RL. Addressing phenoconversion: the Achilles’ heel of personalized medicine. Br J Clin Pharmacol. 2015;79(2):222–40.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138(1):103–41.

    Article  PubMed  CAS  Google Scholar 

  16. Haffen E, Vandel P, Broly F, et al. Citalopram: an interaction study with clomipramine in a patient heterozygous for CYP2D6 genotype. Pharmacopsychiatry. 1999;32(6):232–4.

    Article  PubMed  CAS  Google Scholar 

  17. Kohnke MD, Griese EU, Stosser D, et al. Cytochrome P450 2D6 deficiency and its clinical relevance in a patient treated with risperidone. Pharmacopsychiatry. 2002;35(3):116–8.

    Article  PubMed  CAS  Google Scholar 

  18. Kato D, Kawanishi C, Kishida I, et al. CYP2D6 gene deletion allele in patients with neuroleptic malignant syndrome: preliminary report. Psychiatry Clin Neurosci. 2005;59(4):504–7.

    Article  PubMed  CAS  Google Scholar 

  19. Nara M, Takahashi N, Miura M, et al. Effect of oral itraconazole on the pharmacokinetics of tacrolimus in a hematopoietic stem cell transplant recipient with CYP3A5*3/*3. Am J Hematol. 2010;85(8):634–5.

    Article  PubMed  Google Scholar 

  20. Madadi P, Hildebrandt D, Gong IY, et al. Fatal hydrocodone overdose in a child: pharmacogenetics and drug interactions. Pediatrics. 2010;126(4):e986–9.

    Article  PubMed  Google Scholar 

  21. Suan D, O’Connor K, Booth DR, et al. Voriconazole toxicity related to polymorphisms in CYP2C19. Intern Med J. 2011;41(4):364–5.

    Article  PubMed  CAS  Google Scholar 

  22. Hu M, Mak VW, Tomlinson B. Simvastatin-induced myopathy, the role of interaction with diltiazem and genetic predisposition. J Clin Pharm Ther. 2011;36(3):419–25.

    Article  PubMed  CAS  Google Scholar 

  23. Malingre MM, Godschalk PC, Klein SK. A case report of voriconazole therapy failure in a homozygous ultrarapid CYP2C19*17/*17 patient comedicated with carbamazepine. Br J Clin Pharmacol. 2012;74(1):205–6.

    Article  PubMed  CAS  Google Scholar 

  24. Yang WH, Zeng ZS, Ren XW, et al. Simvastatin-induced myopathy with concomitant use of cyclosporine: case report. Int J Clin Pharmacol Ther. 2011;49(12):772–7.

    Article  PubMed  CAS  Google Scholar 

  25. Fujita Y, Araki T, Okada Y, et al. Analysis of cytochrome P450 gene polymorphism in a lupus nephritis patient in whom tacrolimus blood concentration was markedly elevated after administration of azole antifungal agents. J Clin Pharm Ther. 2013;38(1):74–6.

    Article  PubMed  CAS  Google Scholar 

  26. Zhao W, Fakhoury M, Maisin A, et al. Pharmacogenetic determinant of the drug interaction between tacrolimus and omeprazole. Ther Drug Monit. 2012;34(6):739–41.

    Article  PubMed  CAS  Google Scholar 

  27. Duricova J, Perinova I, Jurckova N, et al. Clinically important interaction between metoprolol and propafenone. Can Fam Phys. 2013;59(4):373–5.

    Google Scholar 

  28. Chua EW, Foulds J, Miller AL, et al. Novel CYP2D6 and CYP2C19 variants identified in a patient with adverse reactions towards venlafaxine monotherapy and dual therapy with nortriptyline and fluoxetine. Pharmacogenet Genomics. 2013;23(9):494–7.

    Article  PubMed  CAS  Google Scholar 

  29. Tomisti L, Del Re M, Bartalena L, et al. Effects of amiodarone, thyroid hormones and CYP2C9 and VKORC1 polymorphisms on warfarin metabolism: a review of the literature. Endocr Pract. 2013;19(6):1043–9.

    Article  PubMed  Google Scholar 

  30. Wu AH, Kearney T. Lack of impairment due to confirmed codeine use prior to a motor vehicle accident: role of pharmacogenomics. J Forensic Leg Med. 2013;20(8):1024–7.

    Article  PubMed  Google Scholar 

  31. Bebawi E, Jouni SS, Tessier AA, et al. A metoprolol-terbinafine combination induced bradycardia. Eur J Drug Metab Pharmacokinet. 2015;40(3):295–9.

    Article  PubMed  CAS  Google Scholar 

  32. Meyer zu Schwabedissen HE, Siegmund W, Kroemer HK, et al. Creatine kinase elevation caused by a combination of fluvastatin and telmisartan in a patient heterozygous for the CYP2C9*3 and ABCC2-24C > T variants: a case report. BMC Res Notes. 2014;7:688.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. van den Berg SAA, van ‘t Veer NE, Emmen JMA, et al. Fluticasone furoate induced iatrogenic Cushing syndrome in a pediatric patient receiving anti-retroviral therapy. Endocrinol Diabetes Metab Case Rep. 2017;2017:16–0158.

    PubMed  PubMed Central  Google Scholar 

  34. Calcagno A, Baietto L, Pagani N, et al. Voriconazole and atazanavir: a CYP2C19-dependent manageable drug-drug interaction. Pharmacogenomics. 2014;15(10):1281–6.

    Article  PubMed  CAS  Google Scholar 

  35. Hebert MF, Lam AY. Diltiazem increases tacrolimus concentrations. Ann Pharmacother. 1999;33(6):680–2.

    Article  PubMed  CAS  Google Scholar 

  36. Ahle GB, Blum AL, Martinek J, et al. Cushing’s syndrome in an 81-year-old patient treated with budesonide and amiodarone. Eur J Gastroenterol Hepatol. 2000;12(9):1041–2.

    Article  PubMed  CAS  Google Scholar 

  37. Lee AJ, Maddix DS. Rhabdomyolysis secondary to a drug interaction between simvastatin and clarithromycin. Ann Pharmacother. 2001;35(1):26–31.

    Article  PubMed  CAS  Google Scholar 

  38. Hsu WC, Chen WH, Chang MT, et al. Colchicine-induced acute myopathy in a patient with concomitant use of simvastatin. Clin Neuropharmacol. 2002;25(5):266–8.

    Article  PubMed  Google Scholar 

  39. Sadaba B, Campanero MA, Quetglas EG, et al. Clinical relevance of sirolimus drug interactions in transplant patients. Transpl Proc. 2004;36(10):3226–8.

    Article  CAS  Google Scholar 

  40. Geronimo-Pardo M, Cuartero-del-Pozo AB, Jimenez-Vizuete JM, et al. Clarithromycin-nifedipine interaction as possible cause of vasodilatory shock. Ann Pharmacother. 2005;39(3):538–42.

    Article  PubMed  Google Scholar 

  41. Akdag I, Ersoy A, Kahvecioglu S, et al. Acute colchicine intoxication during clarithromycin administration in patients with chronic renal failure. J Nephrol. 2006;19(4):515–7.

    PubMed  CAS  Google Scholar 

  42. van der Velden W, Huussen J, Ter Laak H, et al. Colchicine-induced neuromyopathy in a patient with chronic renal failure: the role of clarithromycin. Neth J Med. 2008;66(5):204–6.

    PubMed  Google Scholar 

  43. Priou P, Gagnadoux F, Dehe C, et al. Drug-induced pneumonitis in a patient treated with venlafaxine and propanolol [in French]. Rev Mal Respir. 2008;25(5):610–3.

    Article  PubMed  CAS  Google Scholar 

  44. Eleftheriou G, Bacis G, Fiocchi R, et al. Colchicine-induced toxicity in a heart transplant patient with chronic renal failure. Clin Toxicol (Phila). 2008;46(9):827–30.

    Article  CAS  Google Scholar 

  45. Dopazo C, Bilbao I, Lazaro JL, et al. Severe rhabdomyolysis and acute renal failure secondary to concomitant use of simvastatin with rapamycin plus tacrolimus in liver transplant patient. Transpl Proc. 2009;41(3):1021–4.

    Article  CAS  Google Scholar 

  46. McKinnell J, Tayek JA. Short term treatment with clarithromycin resulting in colchicine-induced rhabdomyolysis. J Clin Rheumatol. 2009;15(6):303–5.

    Article  PubMed  Google Scholar 

  47. Roustit M, Blondel E, Villier C, et al. Symptomatic hypoglycemia associated with trimethoprim/sulfamethoxazole and repaglinide in a diabetic patient. Ann Pharmacother. 2010;44(4):764–7.

    Article  PubMed  Google Scholar 

  48. Gomo C, Coriat R, Faivre L, et al. Pharmacokinetic interaction involving sorafenib and the calcium-channel blocker felodipine in a patient with hepatocellular carcinoma. Invest New Drugs. 2011;29(6):1511–4.

    Article  PubMed  Google Scholar 

  49. Levin TT, Bakr MH, Nikolova T. Case report: delirium due to a diltiazem-fentanyl CYP3A4 drug interaction. Gen Hosp Psychiatry. 2010;32(6):648e9–650e10.

    Article  Google Scholar 

  50. Frankel JK, Packer CD. Cushing’s syndrome due to antiretroviral-budesonide interaction. Ann Pharmacother. 2011;45(6):823–4.

    Article  PubMed  Google Scholar 

  51. Marot A, Morelle J, Chouinard VA, et al. Concomitant use of simvastatin and amiodarone resulting in severe rhabdomyolysis: a case report and review of the literature. Acta Clin Belg. 2011;66(2):134–6.

    PubMed  CAS  Google Scholar 

  52. Hoover WC, Britton LJ, Gardner J, et al. Rapid onset of iatrogenic adrenal insufficiency in a patient with cystic fibrosis-related liver disease treated with inhaled corticosteroids and a moderate CYP3A4 inhibitor. Ann Pharmacother. 2011;45(7–8):e38.

    PubMed  Google Scholar 

  53. Alreja G, Inayatullah S, Goel S, et al. Rhabdomyolysis caused by an unusual interaction between azithromycin and simvastatin. J Cardiovasc Dis Res. 2012;3(4):319–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Holstein A, Kovacs P, Beil W. Severe hypoglycemia due to possible interaction between glibenclamide and sorafenib in a patient with hepatocellular carcinoma. Curr Drug Saf. 2013;8(2):148–52.

    Article  PubMed  CAS  Google Scholar 

  55. Leung JG, Nelson S, Takala CR, et al. Infection and inflammation leading to clozapine toxicity and intensive care: a case series. Ann Pharmacother. 2014;48(6):801–5.

    Article  PubMed  CAS  Google Scholar 

  56. Kanter CT, Luin M, Solas C, et al. Rhabdomyolysis in a hepatitis C virus infected patient treated with telaprevir and simvastatin. Ann Hepatol. 2014;13(4):452–5.

    PubMed  Google Scholar 

  57. Takeuchi S, Kotani Y, Tsujimoto T. Hypotension induced by the concomitant use of a calcium-channel blocker and clarithromycin. BMJ Case Rep. 2017. https://doi.org/10.1136/bcr-2016-218388.

    Article  PubMed Central  PubMed  Google Scholar 

  58. Gasche Y, Daali Y, Fathi M, et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med. 2004;351(27):2827–31.

    Article  PubMed  CAS  Google Scholar 

  59. Tanaka A, Nagamatsu T, Yamaguchi M, et al. Myoclonus after dextromethorphan administration in peritoneal dialysis. Ann Pharmacother. 2011;45(1):e1.

    Article  PubMed  Google Scholar 

  60. Ing Lorenzini K, Calmy A, Ambrosioni J, et al. Serotonin syndrome following drug-drug interactions and CYP2D6 and CYP2C19 genetic polymorphisms in an HIV-infected patient. AIDS. 2012;26(18):2417–8.

    Article  Google Scholar 

  61. Simic I, Potocnjak I, Kraljickovic I, et al. CYP2D6 *6/*6 genotype and drug interactions as cause of haloperidol-induced extrapyramidal symptoms. Pharmacogenomics. 2016;17(13):1385–9.

    Article  PubMed  CAS  Google Scholar 

  62. Forget P, le Polain de Waroux B B, Wallemacq P, et al. Life-threatening dextromethorphan intoxication associated with interaction with amitriptyline in a poor CYP2D6 metabolizer: a single case re-exposure study. J Pain Symptom Manage. 2008;36(1):92–6.

    Article  PubMed  CAS  Google Scholar 

  63. Takahashi K, Motohashi H, Yonezawa A, et al. Lansoprazole-tacrolimus interaction in Japanese transplant recipient with CYP2C19 polymorphism. Ann Pharmacother. 2004;38(5):791–4.

    Article  PubMed  Google Scholar 

  64. Hosohata K, Masuda S, Ogura Y, et al. Interaction between tacrolimus and lansoprazole, but not rabeprazole in living-donor liver transplant patients with defects of CYP2C19 and CYP3A5. Drug Metab Pharmacokinet. 2008;23(2):134–8.

    Article  PubMed  CAS  Google Scholar 

  65. Gorny M, Rohm S, Laer S, et al. Pharmacogenomic adaptation of antiretroviral therapy: overcoming the failure of lopinavir in an African infant with CYP2D6 ultrarapid metabolism. Eur J Clin Pharmacol. 2010;66(1):107–8.

    Article  PubMed  Google Scholar 

  66. Marusic S, Lisicic A, Horvatic I, et al. Atorvastatin-related rhabdomyolysis and acute renal failure in a genetically predisposed patient with potential drug-drug interaction. Int J Clin Pharm. 2012;34(6):825–7.

    Article  PubMed  Google Scholar 

  67. Homma M, Itagaki F, Yuzawa K, et al. Effects of lansoprazole and rabeprazole on tacrolimus blood concentration: case of a renal transplant recipient with CYP2C19 gene mutation. Transplantation. 2002;73(2):303–4.

    Article  PubMed  Google Scholar 

  68. Itagaki F, Homma M, Yuzawa K, et al. Drug interaction of tacrolimus and proton pump inhibitors in renal transplant recipients with CYP2C19 gene mutation. Transplant Proc. 2002;34(7):2777–8.

    Article  PubMed  CAS  Google Scholar 

  69. Grozinger M, Hartter S, Hiemke C, et al. Interaction of modafinil and clomipramine as comedication in a narcoleptic patient. Clin Neuropharmacol. 1998;21(2):127–9.

    PubMed  CAS  Google Scholar 

  70. Spina E, Scordo MG, Avenoso A, et al. Adverse drug interaction between risperidone and carbamazepine in a patient with chronic schizophrenia and deficient CYP2D6 activity. J Clin Psychopharmacol. 2001;21(1):108–9.

    Article  PubMed  CAS  Google Scholar 

  71. Hasse B, Gunthard HF, Bleiber G, et al. Efavirenz intoxication due to slow hepatic metabolism. Clin Infect Dis. 2005;40(3):e22–3.

    Article  PubMed  CAS  Google Scholar 

  72. Lee HK, Lewis LD, Tsongalis GJ, et al. Negative urine opioid screening caused by rifampin-mediated induction of oxycodone hepatic metabolism. Clin Chim Acta. 2006;367(1–2):196–200.

    Article  PubMed  CAS  Google Scholar 

  73. Elkalioubie A, Allorge D, Robriquet L, et al. Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer. Eur J Clin Pharmacol. 2011;67(8):855–8.

    Article  PubMed  CAS  Google Scholar 

  74. Geber C, Ostad Haji E, Schlicht K, et al. Severe tremor after cotrimoxazole-induced elevation of venlafaxine serum concentrations in a patient with major depressive disorder. Ther Drug Monit. 2013;35(3):279–82.

    Article  PubMed  Google Scholar 

  75. Motta I, Calcagno A, Baietto L, et al. A probable drug-to-drug interaction between voriconazole and haloperidol in a CYP2C19 poor metabolizing patient [corrected]. Infez Med. 2015;23(4):367–9.

    PubMed  Google Scholar 

  76. Flockhart DA. Drug Interactions: Cytochromes P450 Drug Interaction Table. Indiana University School of Medicine (2007). http://medicine.iupui.edu/clinpharm/ddis/main-table. Accessed 8 Feb 2018.

  77. Edsbacker S, Andersson T. Pharmacokinetics of budesonide (Entocort EC) capsules for Crohn’s disease. Clin Pharmacokinet. 2004;43(12):803–21.

    Article  PubMed  Google Scholar 

  78. Wojcikowski J, Boksa J, Daniel WA. Main contribution of the cytochrome P450 isoenzyme 1A2 (CYP1A2) to N-demethylation and 5-sulfoxidation of the phenothiazine neuroleptic chlorpromazine in human liver: a comparison with other phenothiazines. Biochem Pharmacol. 2010;80(8):1252–9.

    Article  PubMed  CAS  Google Scholar 

  79. Yoshii K, Kobayashi K, Tsumuji M, et al. Identification of human cytochrome P450 isoforms involved in the 7-hydroxylation of chlorpromazine by human liver microsomes. Life Sci. 2000;67(2):175–84.

    Article  PubMed  CAS  Google Scholar 

  80. Nielsen KK, Flinois JP, Beaune P, et al. The biotransformation of clomipramine in vitro, identification of the cytochrome P450 s responsible for the separate metabolic pathways. J Pharmacol Exp Ther. 1996;277(3):1659–64.

    PubMed  CAS  Google Scholar 

  81. Clozaril Drug Information. Novartis. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019758s073lbl.pdf. Accessed 9 Feb 2018.

  82. Terkeltaub RA. Colchicine update: 2008. Semin Arthritis Rheum. 2009;38(6):411–9.

    Article  PubMed  CAS  Google Scholar 

  83. Molden E, Asberg A, Christensen H. CYP2D6 is involved in O-demethylation of diltiazem. An in vitro study with transfected human liver cells. Eur J Clin Pharmacol. 2000;56(8):575–9.

    Article  PubMed  CAS  Google Scholar 

  84. Molden E, Johansen PW, Boe GH, et al. Pharmacokinetics of diltiazem and its metabolites in relation to CYP2D6 genotype. Clin Pharmacol Ther. 2002;72(3):333–42.

    Article  PubMed  CAS  Google Scholar 

  85. Sutton D, Butler AM, Nadin L, et al. Role of CYP3A4 in human hepatic diltiazem N-demethylation: inhibition of CYP3A4 activity by oxidized diltiazem metabolites. J Pharmacol Exp Ther. 1997;282(1):294–300.

    PubMed  CAS  Google Scholar 

  86. Ward BA, Gorski JC, Jones DR, et al. The cytochrome P450 2B6 (CYP2B6) is the main catalyst of efavirenz primary and secondary metabolism: implication for HIV/AIDS therapy and utility of efavirenz as a substrate marker of CYP2B6 catalytic activity. J Pharmacol Exp Ther. 2003;306(1):287–300.

    Article  PubMed  CAS  Google Scholar 

  87. Lexapro Drug Information. Allergan. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021323s032,021365s023lbl.pdf. Accessed 23 Aug 2017.

  88. Flonase Drug Information. GlaxoSmithKline. http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/020121s028lbl.pdf. Accessed 23 Aug 2017.

  89. Zhou L, Naraharisetti SB, Liu L, et al. Contributions of human cytochrome P450 enzymes to glyburide metabolism. Biopharm Drug Dispos. 2010;31(4):228–42.

    PubMed  PubMed Central  CAS  Google Scholar 

  90. Zharikova OL, Fokina VM, Nanovskaya TN, et al. Identification of the major human hepatic and placental enzymes responsible for the biotransformation of glyburide. Biochem Pharmacol. 2009;78(12):1483–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Diaβeta Drug information. Sanofi-Aventis. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017532s030lbl.pdf. Accessed 9 Feb 2018.

  92. Hutchinson MR, Menelaou A, Foster DJ, et al. CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes. Br J Clin Pharmacol. 2004;57(3):287–97.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Kumar GN, Dykstra J, Roberts EM, et al. Potent inhibition of the cytochrome P-450 3A-mediated human liver microsomal metabolism of a novel HIV protease inhibitor by ritonavir: a positive drug-drug interaction. Drug Metab Dispos. 1999;27(8):902–8.

    PubMed  CAS  Google Scholar 

  94. Olesen OV, Linnet K. Hydroxylation and demethylation of the tricyclic antidepressant nortriptyline by cDNA-expressed human cytochrome P-450 isozymes. Drug Metab Dispos. 1997;25(6):740–4.

    PubMed  CAS  Google Scholar 

  95. Venkatakrishnan K, von Moltke LL, Greenblatt DJ. Nortriptyline E-10-hydroxylation in vitro is mediated by human CYP2D6 (high affinity) and CYP3A4 (low affinity): implications for interactions with enzyme-inducing drugs. J Clin Pharmacol. 1999;39(6):567–77.

    Article  PubMed  CAS  Google Scholar 

  96. Samer CF, Daali Y, Wagner M, et al. The effects of CYP2D6 and CYP3A activities on the pharmacokinetics of immediate release oxycodone. Br J Pharmacol. 2010;160(4):907–18.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Sall C, Houston JB, Galetin A. A comprehensive assessment of repaglinide metabolic pathways: impact of choice of in vitro system and relative enzyme contribution to in vitro clearance. Drug Metab Dispos. 2012;40(7):1279–89.

    Article  PubMed  CAS  Google Scholar 

  98. Nevaxar FDA Drug Approval Package. Bayer. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_NexavarTOC.cfm. Accessed 12 Feb 2018.

  99. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879–923.

    Article  PubMed  CAS  Google Scholar 

  100. Fogelman SM, Schmider J, Venkatakrishnan K, et al. O- and N-demethylation of venlafaxine in vitro by human liver microsomes and by microsomes from cDNA-transfected cells: effect of metabolic inhibitors and SSRI antidepressants. Neuropsychopharmacology. 1999;20(5):480–90.

    Article  PubMed  CAS  Google Scholar 

  101. 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.

    Article  PubMed  CAS  Google Scholar 

  102. Ufer M. Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol. Clin Pharmacokinet. 2005;44(12):1227–46.

    Article  PubMed  CAS  Google Scholar 

  103. O’Reilly RA, Trager WF, Rettie AE, et al. Interaction of amiodarone with racemic warfarin and its separated enantiomorphs in humans. Clin Pharmacol Ther. 1987;42(3):290–4.

    Article  PubMed  Google Scholar 

  104. Abilify Drug Information. Otsuka. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021436s038,021713s030,021729s022,021866s023lbl.pdf. Accessed 23 Aug 2017.

  105. Perloff ES, Duan SX, Skolnik PR, et al. Atazanavir: effects on P-glycoprotein transport and CYP3A metabolism in vitro. Drug Metab Dispos. 2005;33(6):764–70.

    Article  PubMed  CAS  Google Scholar 

  106. Westphal JF. Macrolide-induced clinically relevant drug interactions with cytochrome P-450A (CYP) 3A4: an update focused on clarithromycin, azithromycin and dirithromycin. Br J Clin Pharmacol. 2000;50(4):285–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Shin JG, Soukhova N, Flockhart DA. Effect of antipsychotic drugs on human liver cytochrome P-450 (CYP) isoforms in vitro: preferential inhibition of CYP2D6. Drug Metab Dispos. 1999;27(9):1078–84.

    PubMed  CAS  Google Scholar 

  108. Suzuki Y, Someya T, Shimoda K, et al. Importance of the cytochrome P450 2D6 genotype for the drug metabolic interaction between chlorpromazine and haloperidol. Ther Drug Monit. 2001;23(4):363–8.

    Article  PubMed  CAS  Google Scholar 

  109. Spina E, Martines C, Caputi AP, et al. Debrisoquine oxidation phenotype during neuroleptic monotherapy. Eur J Clin Pharmacol. 1991;41(5):467–70.

    Article  PubMed  CAS  Google Scholar 

  110. Vlase L, Popa A, Neag M, et al. Pharmacokinetic interaction between zolpidem and ciprofloxacin in healthy volunteers. Eur J Drug Metab Pharmacokinet. 2011;35(3–4):83–7.

    Article  PubMed  CAS  Google Scholar 

  111. Gram LF, Hansen MG, Sindrup SH, et al. Citalopram: interaction studies with levomepromazine, imipramine, and lithium. Ther Drug Monit. 1993;15(1):18–24.

    Article  PubMed  CAS  Google Scholar 

  112. Kajosaari LI, Niemi M, Neuvonen M, et al. Cyclosporine markedly raises the plasma concentrations of repaglinide. Clin Pharmacol Ther. 2005;78(4):388–99.

    Article  PubMed  CAS  Google Scholar 

  113. Back D, Sekar V, Hoetelmans RM. Darunavir: pharmacokinetics and drug interactions. Antivir Ther. 2008;13(1):1–13.

    PubMed  CAS  Google Scholar 

  114. Yasui-Furukori N, Takahata T, Nakagami T, et al. Different inhibitory effect of fluvoxamine on omeprazole metabolism between CYP2C19 genotypes. Br J Clin Pharmacol. 2004;57(4):487–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Galetin A, Clarke SE, Houston JB. Quinidine and haloperidol as modifiers of CYP3A4 activity: multisite kinetic model approach. Drug Metab Dispos. 2002;30(12):1512–22.

    Article  PubMed  CAS  Google Scholar 

  116. Shin JG, Kane K, Flockhart DA. Potent inhibition of CYP2D6 by haloperidol metabolites: stereoselective inhibition by reduced haloperidol. Br J Clin Pharmacol. 2001;51(1):45–52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Yanagida Y, Watanabe M, Takeba Y, et al. Potential of lansoprazole as a novel probe for cytochrome P450 3A activity by measuring lansoprazole sulfone in human liver microsomes. Biol Pharm Bull. 2009;32(8):1422–6.

    Article  PubMed  CAS  Google Scholar 

  118. Syvalahti EK, Lindberg R, Kallio J, et al. Inhibitory effects of neuroleptics on debrisoquine oxidation in man. Br J Clin Pharmacol. 1986;22(1):89–92.

    PubMed  PubMed Central  CAS  Google Scholar 

  119. Robertson P, DeCory HH, Madan A, et al. In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil. Drug Metab Dispos. 2000;28(6):664–71.

    PubMed  CAS  Google Scholar 

  120. Hamelin BA, Bouayad A, Drolet B, et al. In vitro characterization of cytochrome P450 2D6 inhibition by classic histamine H1 receptor antagonists. Drug Metab Dispos. 1998;26(6):536–9.

    PubMed  CAS  Google Scholar 

  121. Johnson JA, Herring VL, Wolfe MS, et al. CYP1A2 and CYP2D6 4-hydroxylate propranolol and both reactions exhibit racial differences. J Pharmacol Exp Ther. 2000;294(3):1099–105.

    PubMed  CAS  Google Scholar 

  122. Filppula AM, Neuvonen PJ, Backman JT. In vitro assessment of time-dependent inhibitory effects on CYP2C8 and CYP3A activity by fourteen protein kinase inhibitors. Drug Metab Dispos. 2014;42(7):1202–9.

    Article  PubMed  CAS  Google Scholar 

  123. Chapron B, Risler L, Phillips B, et al. Reversible, time-dependent inhibition of CYP3A-mediated metabolism of midazolam and tacrolimus by telaprevir in human liver microsomes. J Pharm Pharm Sci. 2015;18(1):101–11.

    Article  PubMed  CAS  Google Scholar 

  124. Garg V, Kauffman RS, Beaumont M, et al. Telaprevir: pharmacokinetics and drug interactions. Antivir Ther. 2012;17(7):1211–21.

    Article  PubMed  CAS  Google Scholar 

  125. Kamiyama E, Yoshigae Y, Kasuya A, et al. Inhibitory effects of angiotensin receptor blockers on CYP2C9 activity in human liver microsomes. Drug Metab Pharmacokinet. 2007;22(4):267–75.

    Article  PubMed  CAS  Google Scholar 

  126. Ll A, Berecz R, de la Rubia A, et al. Effect of thioridazine dosage on the debrisoquine hydroxylation phenotype in psychiatric patients with different CYP2D6 genotypes. Ther Drug Monit. 2001;23(6):616–20.

    Article  Google Scholar 

  127. Wen X, Wang JS, Kivisto KT, et al. In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9). Br J Clin Pharmacol. 2001;52(5):547–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Saari TI, Laine K, Leino K, et al. Effect of voriconazole on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam. Clin Pharmacol Ther. 2006;79(4):362–70.

    Article  PubMed  CAS  Google Scholar 

  129. Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev. 2009;41(2):89–295.

    Article  PubMed  CAS  Google Scholar 

  130. Valenzuela B, Rebollo J, Perez T, et al. Effect of grapefruit juice on the pharmacokinetics of docetaxel in cancer patients: a case report. Br J Clin Pharmacol. 2011;72(6):978–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Dunnenberger HM, Crews KR, Hoffman JM, et al. Preemptive clinical pharmacogenetics implementation: current programs in five US medical centers. Annu Rev Pharmacol Toxicol. 2015;55:89–106.

    Article  PubMed  CAS  Google Scholar 

  132. Van Driest SL, Shi Y, Bowton EA, et al. Clinically actionable genotypes among 10,000 patients with preemptive pharmacogenomic testing. Clin Pharmacol Ther. 2014;95(4):423–31.

    Article  PubMed  CAS  Google Scholar 

  133. Goh LL, Lim CW, Sim WC, et al. Analysis of genetic variation in CYP450 genes for clinical implementation. PLoS One. 2017;12(1):e0169233.

    Article  PubMed  PubMed Central  Google Scholar 

  134. van der Wouden CH, Cambon-Thomsen A, Cecchin E, et al. Implementing pharmacogenomics in Europe: design and implementation strategy of the ubiquitous pharmacogenomics consortium. Clin Pharmacol Ther. 2017;101(3):341–58.

    Article  PubMed  Google Scholar 

  135. Gottesman O, Scott SA, Ellis SB, et al. The CLIPMERGE PGx Program: clinical implementation of personalized medicine through electronic health records and genomics-pharmacogenomics. Clin Pharmacol Ther. 2013;94(2):214–7.

    Article  PubMed  CAS  Google Scholar 

  136. Rasmussen-Torvik LJ, Stallings SC, Gordon AS, et al. Design and anticipated outcomes of the eMERGE-PGx project: a multicenter pilot for preemptive pharmacogenomics in electronic health record systems. Clin Pharmacol Ther. 2014;96(4):482–9.

    Article  PubMed  CAS  Google Scholar 

  137. Eadon MT, Desta Z, Levy KD, et al. Implementation of a pharmacogenomics consult service to support the INGENIOUS trial. Clin Pharmacol Ther. 2016;100(1):63–6.

    Article  PubMed  CAS  Google Scholar 

  138. Hoffman JM, Haidar CE, Wilkinson MR, et al. PG4KDS: a model for the clinical implementation of pre-emptive pharmacogenetics. Am J Med Genet C Semin Med Genet. 2014;166C(1):45–55.

    Article  PubMed  Google Scholar 

  139. Bielinski SJ, Olson JE, Pathak J, et al. Preemptive genotyping for personalized medicine: design of the right drug, right dose, right time-using genomic data to individualize treatment protocol. Mayo Clin Proc. 2014;89(1):25–33.

    Article  PubMed  Google Scholar 

  140. Hocum BT, White JR Jr, Heck JW, et al. Cytochrome P-450 gene and drug interaction analysis in patients referred for pharmacogenetic testing. Am J Health Syst Pharm. 2016;73(2):61–7.

    Article  PubMed  CAS  Google Scholar 

  141. Bahar MA, Setiawan D, Hak E, et al. Pharmacogenetics of drug-drug interaction and drug-drug-gene interaction: a systematic review on CYP2C9, CYP2C19 and CYP2D6. Pharmacogenomics. 2017;18(7):701–39.

    Article  PubMed  CAS  Google Scholar 

  142. Venkatakrishnan K, Obach RS. In vitro-in vivo extrapolation of CYP2D6 inactivation by paroxetine: prediction of nonstationary pharmacokinetics and drug interaction magnitude. Drug Metab Dispos. 2005;33(6):845–52.

    Article  PubMed  CAS  Google Scholar 

  143. Azuma J, Hasunuma T, Kubo M, et al. The relationship between clinical pharmacokinetics of aripiprazole and CYP2D6 genetic polymorphism: effects of CYP enzyme inhibition by coadministration of paroxetine or fluvoxamine. Eur J Clin Pharmacol. 2012;68(1):29–37.

    Article  PubMed  CAS  Google Scholar 

  144. Lim KS, Cho JY, Jang IJ, et al. Pharmacokinetic interaction of flecainide and paroxetine in relation to the CYP2D6*10 allele in healthy Korean subjects. Br J Clin Pharmacol. 2008;66(5):660–6.

    PubMed  PubMed Central  CAS  Google Scholar 

  145. Lee LS, Nafziger AN, Bertino JS Jr. Evaluation of inhibitory drug interactions during drug development: genetic polymorphisms must be considered. Clin Pharmacol Ther. 2005;78(1):1–6.

    Article  PubMed  CAS  Google Scholar 

  146. Damy T, Pousset F, Caplain H, et al. Pharmacokinetic and pharmacodynamic interactions between metoprolol and dronedarone in extensive and poor CYP2D6 metabolizers healthy subjects. Fundam Clin Pharmacol. 2004;18(1):113–23.

    Article  PubMed  CAS  Google Scholar 

  147. LLerena A, Berecz R, de la Rubia A, et al. Effect of thioridazine dosage on the debrisoquine hydroxylation phenotype in psychiatric patients with different CYP2D6 genotypes. Ther Drug Monit. 2001;23(6):616–20.

    Article  PubMed  CAS  Google Scholar 

  148. Kumar V, Brundage RC, Oetting WS, et al. Differential genotype dependent inhibition of CYP2C9 in humans. Drug Metab Dispos. 2008;36(7):1242–8.

    Article  PubMed  CAS  Google Scholar 

  149. Andersson ML, Eliasson E, Lindh JD. A clinically significant interaction between warfarin and simvastatin is unique to carriers of the CYP2C9*3 allele. Pharmacogenomics. 2012;13(7):757–62.

    Article  PubMed  CAS  Google Scholar 

  150. Preskorn SH, Kane CP, Lobello K, et al. Cytochrome P450 2D6 phenoconversion is common in patients being treated for depression: implications for personalized medicine. J Clin Psychiatry. 2013;74(6):614–21.

    Article  PubMed  CAS  Google Scholar 

  151. Gschwind L, Rollason V, Boehlen F, et al. Impact of CYP2C9 polymorphisms on the vulnerability to pharmacokinetic drug-drug interactions during acenocoumarol treatment. Pharmacogenomics. 2013;14(7):745–53.

    Article  PubMed  CAS  Google Scholar 

  152. Storelli F, Matthey A, Lenglet S, et al. Impact of CYP2D6 functional allelic variations on phenoconversion and drug-drug interactions. Clin Pharmacol Ther. 2017. https://doi.org/10.1002/cpt.889.

    Article  PubMed  Google Scholar 

  153. Imamura CK, Furihata K, Okamoto S, et al. Impact of cytochrome P450 2C19 polymorphisms on the pharmacokinetics of tacrolimus when coadministered with voriconazole. J Clin Pharmacol. 2016;56(4):408–13.

    Article  PubMed  CAS  Google Scholar 

  154. Tod M, Nkoud-Mongo C, Gueyffier F. Impact of genetic polymorphism on drug-drug interactions mediated by cytochromes: a general approach. AAPS J. 2013;15(4):1242–52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Bolley R, Zulke C, Kammerl M, et al. Tacrolimus-induced nephrotoxicity unmasked by induction of the CYP3A4 system with St John’s wort. Transplantation. 2002;73(6):1009.

    Article  PubMed  Google Scholar 

  156. Vieira MD, Kim MJ, Apparaju S, et al. PBPK model describes the effects of comedication and genetic polymorphism on systemic exposure of drugs that undergo multiple clearance pathways. Clin Pharmacol Ther. 2014;95(5):550–7.

    Article  PubMed  CAS  Google Scholar 

  157. Hill NR, Fatoba ST, Oke JL, et al. Global prevalence of chronic kidney disease—a systematic review and meta-analysis. PLoS One. 2016;11(7):e0158765.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Webster AC, Nagler EV, Morton RL, et al. Chronic kidney disease. Lancet. 2017;389(10075):1238–52.

    Article  PubMed  Google Scholar 

  159. Basile DP, Anderson MD, Sutton TA. Pathophysiology of acute kidney injury. Compr Physiol. 2012;2(2):1303–53.

    PubMed  PubMed Central  Google Scholar 

  160. Miners JO, Yang X, Knights KM, et al. The role of the kidney in drug elimination: transport, metabolism, and the impact of kidney disease on drug clearance. Clin Pharmacol Ther. 2017;102(3):436–49.

    Article  PubMed  CAS  Google Scholar 

  161. Guevin C, Michaud J, Naud J, et al. Down-regulation of hepatic cytochrome p450 in chronic renal failure: role of uremic mediators. Br J Pharmacol. 2002;137(7):1039–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Rege B, Krieg R, Gao N, et al. Down-regulation of hepatic CYP3A in chronic renal insufficiency. Pharm Res. 2003;20(10):1600–6.

    Article  PubMed  CAS  Google Scholar 

  163. Michaud J, Dube P, Naud J, et al. Effects of serum from patients with chronic renal failure on rat hepatic cytochrome P450. Br J Pharmacol. 2005;144(8):1067–77.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  164. Leblond FA, Giroux L, Villeneuve JP, et al. Decreased in vivo metabolism of drugs in chronic renal failure. Drug Metab Dispos. 2000;28(11):1317–20.

    PubMed  CAS  Google Scholar 

  165. Velenosi TJ, Fu AY, Luo S, et al. Down-regulation of hepatic CYP3A and CYP2C mediated metabolism in rats with moderate chronic kidney disease. Drug Metab Dispos. 2012;40(8):1508–14.

    Article  PubMed  CAS  Google Scholar 

  166. Leblond FA, Petrucci M, Dube P, et al. Downregulation of intestinal cytochrome p450 in chronic renal failure. J Am Soc Nephrol. 2002;13(6):1579–85.

    Article  PubMed  CAS  Google Scholar 

  167. Dani M, Boisvert C, Michaud J, et al. Down-regulation of liver drug-metabolizing enzymes in a murine model of chronic renal failure. Drug Metab Dispos. 2010;38(3):357–60.

    Article  PubMed  CAS  Google Scholar 

  168. Dreisbach AW, Japa S, Gebrekal AB, et al. Cytochrome P4502C9 activity in end-stage renal disease. Clin Pharmacol Ther. 2003;73(5):475–7.

    Article  PubMed  CAS  Google Scholar 

  169. Dowling TC, Briglia AE, Fink JC, et al. Characterization of hepatic cytochrome p4503A activity in patients with end-stage renal disease. Clin Pharmacol Ther. 2003;73(5):427–34.

    Article  PubMed  CAS  Google Scholar 

  170. Rowland Yeo K, Aarabi M, Jamei M, et al. Modeling and predicting drug pharmacokinetics in patients with renal impairment. Expert Rev Clin Pharmacol. 2011;4(2):261–74.

    Article  PubMed  Google Scholar 

  171. Yeung CK, Shen DD, Thummel KE, et al. Effects of chronic kidney disease and uremia on hepatic drug metabolism and transport. Kidney Int. 2014;85(3):522–8.

    Article  PubMed  CAS  Google Scholar 

  172. US FDA. Guidance for Industry. Pharmacokinetics in patients with impaired renal function—study design, data analysis, and impact on dosing and labeling. 2010. http://www.fda.gov/downloads/drugs/guidances/ucm204959.pdf. Accessed 19 Sep 2017.

  173. European Medicines Agency. Guideline on the evaluatin of the pharmacokinetics of medicinal products in patients with decreased renal function. 2014. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/02/WC500162133.pdf. Accessed 13 Sep 2017.

  174. Nolin TD, Naud J, Leblond FA, et al. Emerging evidence of the impact of kidney disease on drug metabolism and transport. Clin Pharmacol Ther. 2008;83(6):898–903.

    Article  PubMed  CAS  Google Scholar 

  175. Zocor Drug Information. MSD Merck Sharp & Dohme. http://www.swissmedicinfo.ch/default.aspx. Accessed 13 Sep 2017.

  176. Silva M, Matthews ML, Jarvis C, et al. Meta-analysis of drug-induced adverse events associated with intensive-dose statin therapy. Clin Ther. 2007;29(2):253–60.

    Article  PubMed  CAS  Google Scholar 

  177. Zhao P, Vieira Mde L, Grillo JA, et al. Evaluation of exposure change of nonrenally eliminated drugs in patients with chronic kidney disease using physiologically based pharmacokinetic modeling and simulation. J Clin Pharmacol. 2012;52(1 Suppl):91S–108S.

    Article  PubMed  CAS  Google Scholar 

  178. Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol. 2008;64(12):1147–61.

    Article  PubMed  CAS  Google Scholar 

  179. Edginton AN, Willmann S. Physiology-based simulations of a pathological condition: prediction of pharmacokinetics in patients with liver cirrhosis. Clin Pharmacokinet. 2008;47(11):743–52.

    Article  PubMed  Google Scholar 

  180. Gines P, Guevara M, Arroyo V, et al. Hepatorenal syndrome. Lancet. 2003;362(9398):1819–27.

    Article  PubMed  CAS  Google Scholar 

  181. George J, Murray M, Byth K, et al. Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease. Hepatology. 1995;21(1):120–8.

    PubMed  CAS  Google Scholar 

  182. Palatini P, De Martin S. Pharmacokinetic drug interactions in liver disease: an update. World J Gastroenterol. 2016;22(3):1260–78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  183. Orlando R, Piccoli P, De Martin S, et al. Cytochrome P450 1A2 is a major determinant of lidocaine metabolism in vivo: effects of liver function. Clin Pharmacol Ther. 2004;75(1):80–8.

    Article  PubMed  CAS  Google Scholar 

  184. Orlando R, Padrini R, Perazzi M, et al. Liver dysfunction markedly decreases the inhibition of cytochrome P450 1A2-mediated theophylline metabolism by fluvoxamine. Clin Pharmacol Ther. 2006;79(5):489–99.

    Article  PubMed  CAS  Google Scholar 

  185. Floreani M, De Martin S, Gabbia D, et al. Severe liver cirrhosis markedly reduces AhR-mediated induction of cytochrome P450 in rats by decreasing the transcription of target genes. PLoS One. 2013;8(4):e61983.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  186. Iyer R, Fetterly G, Lugade A, et al. Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother. 2010;11(11):1943–55.

    Article  PubMed  CAS  Google Scholar 

  187. Lathia C, Lettieri J, Cihon F, et al. Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics. Cancer Chemother Pharmacol. 2006;57(5):685–92.

    Article  PubMed  CAS  Google Scholar 

  188. Ye L, Yang X, Guo E, et al. Sorafenib metabolism is significantly altered in the liver tumor tissue of hepatocellular carcinoma patient. PLoS One. 2014;9(5):e96664.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  189. Steelandt J, Jean-Bart E, Goutelle S, et al. A prediction model of drug exposure in cirrhotic patients according to child-pugh classification. Clin Pharmacokinet. 2015;54(12):1245–58.

    Article  PubMed  Google Scholar 

  190. Johnson TN, Boussery K, Rowland-Yeo K, et al. A semi-mechanistic model to predict the effects of liver cirrhosis on drug clearance. Clin Pharmacokinet. 2010;49(3):189–206.

    Article  PubMed  CAS  Google Scholar 

  191. Wagner C, Zhao P, Arya V, et al. Physiologically based pharmacokinetic modeling for predicting the effect of intrinsic and extrinsic factors on darunavir or lopinavir exposure coadministered with ritonavir. J Clin Pharmacol. 2017;57(10):1295–304.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  192. Coutant DE, Kulanthaivel P, Turner PK, et al. Understanding disease-drug interactions in cancer patients: implications for dosing within the therapeutic window. Clin Pharmacol Ther. 2015;98(1):76–86.

    Article  PubMed  CAS  Google Scholar 

  193. Xu Y, Hijazi Y, Wolf A, et al. Physiologically based pharmacokinetic model to assess the influence of blinatumomab-mediated cytokine elevations on cytochrome P450 enzyme activity. CPT Pharmacom Syst Pharmacol. 2015;4(9):507–15.

    Article  CAS  Google Scholar 

  194. Morgan ET, Goralski KB, Piquette-Miller M, et al. Regulation of drug-metabolizing enzymes and transporters in infection, inflammation, and cancer. Drug Metab Dispos. 2008;36(2):205–16.

    Article  PubMed  CAS  Google Scholar 

  195. Klein M, Thomas M, Hofmann U, et al. A systematic comparison of the impact of inflammatory signaling on absorption, distribution, metabolism, and excretion gene expression and activity in primary human hepatocytes and HepaRG cells. Drug Metab Dispos. 2015;43(2):273–83.

    Article  PubMed  CAS  Google Scholar 

  196. Rubin K, Janefeldt A, Andersson L, et al. HepaRG cells as human-relevant in vitro model to study the effects of inflammatory stimuli on cytochrome P450 isoenzymes. Drug Metab Dispos. 2015;43(1):119–25.

    Article  PubMed  CAS  Google Scholar 

  197. Dickmann LJ, Patel SK, Wienkers LC, et al. Effects of interleukin 1beta (IL-1beta) and IL-1beta/interleukin 6 (IL-6) combinations on drug metabolizing enzymes in human hepatocyte culture. Curr Drug Metab. 2012;13(7):930–7.

    Article  PubMed  CAS  Google Scholar 

  198. Mimura H, Kobayashi K, Xu L, et al. Effects of cytokines on CYP3A4 expression and reversal of the effects by anti-cytokine agents in the three-dimensionally cultured human hepatoma cell line FLC-4. Drug Metab Pharmacokinet. 2015;30(1):105–10.

    Article  PubMed  CAS  Google Scholar 

  199. Dickmann LJ, Patel SK, Rock DA, et al. Effects of interleukin-6 (IL-6) and an anti-IL-6 monoclonal antibody on drug-metabolizing enzymes in human hepatocyte culture. Drug Metab Dispos. 2011;39(8):1415–22.

    Article  PubMed  CAS  Google Scholar 

  200. Yang J, Hao C, Yang D, et al. Pregnane X receptor is required for interleukin-6-mediated down-regulation of cytochrome P450 3A4 in human hepatocytes. Toxicol Lett. 2010;197(3):219–26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  201. Harvey RD, Morgan ET. Cancer, inflammation, and therapy: effects on cytochrome p450-mediated drug metabolism and implications for novel immunotherapeutic agents. Clin Pharmacol Ther. 2014;96(4):449–57.

    Article  PubMed  CAS  Google Scholar 

  202. Schmitt C, Kuhn B, Zhang X, et al. Disease-drug-drug interaction involving tocilizumab and simvastatin in patients with rheumatoid arthritis. Clin Pharmacol Ther. 2011;89(5):735–40.

    Article  PubMed  CAS  Google Scholar 

  203. Lee EB, Daskalakis N, Xu C, et al. Disease-drug interaction of sarilumab and simvastatin in patients with rheumatoid arthritis. Clin Pharmacokinet. 2017;56(6):607–15.

    Article  PubMed  CAS  Google Scholar 

  204. Zhuang Y, de Vries DE, Xu Z, et al. Evaluation of disease-mediated therapeutic protein-drug interactions between an anti-interleukin-6 monoclonal antibody (sirukumab) and cytochrome P450 activities in a phase 1 study in patients with rheumatoid arthritis using a cocktail approach. J Clin Pharmacol. 2015;55(12):1386–94.

    Article  PubMed  CAS  Google Scholar 

  205. Jiang X, Zhuang Y, Xu Z, et al. Development of a physiologically based pharmacokinetic model to predict disease-mediated therapeutic protein-drug interactions: modulation of multiple cytochrome P450 enzymes by interleukin-6. AAPS J. 2016;18(3):767–76.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  206. Machavaram KK, Almond LM, Rostami-Hodjegan A, et al. A physiologically based pharmacokinetic modeling approach to predict disease-drug interactions: suppression of CYP3A by IL-6. Clin Pharmacol Ther. 2013;94(2):260–8.

    Article  PubMed  CAS  Google Scholar 

  207. Muntane-Relat J, Ourlin JC, Domergue J, et al. Differential effects of cytokines on the inducible expression of CYP1A1, CYP1A2, and CYP3A4 in human hepatocytes in primary culture. Hepatology. 1995;22(4 Pt 1):1143–53.

    Article  PubMed  CAS  Google Scholar 

  208. Pascussi JM, Gerbal-Chaloin S, Pichard-Garcia L, et al. Interleukin-6 negatively regulates the expression of pregnane X receptor and constitutively activated receptor in primary human hepatocytes. Biochem Biophys Res Commun. 2000;274(3):707–13.

    Article  PubMed  CAS  Google Scholar 

  209. Missiakos O, Baysari MT, Day RO. Identifying effective computerized strategies to prevent drug-drug interactions in hospital: a user-centered approach. Int J Med Inform. 2015;84(8):595–600.

    Article  PubMed  Google Scholar 

  210. Boussadi A, Caruba T, Karras A, et al. Validity of a clinical decision rule-based alert system for drug dose adjustment in patients with renal failure intended to improve pharmacists’ analysis of medication orders in hospitals. Int J Med Inform. 2013;82(10):964–72.

    Article  PubMed  CAS  Google Scholar 

  211. Zheng WY, Richardson LC, Li L, et al. Drug-drug interactions and their harmful effects in hospitalised patients: a systematic review and meta-analysis. Eur J Clin Pharmacol. 2018;74(1):15–27.

    Article  PubMed  CAS  Google Scholar 

  212. Carli D. Impact des aides à la décision informatisée sur la qualité des soins. Geneva: University of Geneva; 2016.

    Google Scholar 

  213. Bosilkovska M, Samer CF, Deglon J, et al. Geneva cocktail for cytochrome p450 and P-glycoprotein activity assessment using dried blood spots. Clin Pharmacol Ther. 2014;96(3):349–59.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  214. Stanek EJ, Sanders CL, Taber KA, et al. Adoption of pharmacogenomic testing by US physicians: results of a nationwide survey. Clin Pharmacol Ther. 2012;91(3):450–8.

    Article  PubMed  CAS  Google Scholar 

  215. O’Donnell PH, Danahey K, Jacobs M, et al. Adoption of a clinical pharmacogenomics implementation program during outpatient care: initial results of the University of Chicago “1,200 Patients Project”. Am J Med Genet C Semin Med Genet. 2014;166C(1):68–75.

    Article  PubMed  Google Scholar 

  216. Fontana P, Cattaneo M, Combescure C, et al. Tailored thienopyridine therapy: no urgency for CYP2C19 genotyping. J Am Heart Assoc. 2013;2(2):e000131.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  217. Reny JL, Fontana P, Hochholzer W, et al. Vascular risk levels affect the predictive value of platelet reactivity for the occurrence of MACE in patients on clopidogrel. Systematic review and meta-analysis of individual patient data. Thromb Haemost. 2016;115(4):844–55.

    PubMed  Google Scholar 

  218. Patel C, Rathi C, Venkatakrishnan K. Should race-genotype interactions be considered in the global development of CYP2C19 Substrates? A proposed framework using physiologically based pharmacokinetic modeling. J Clin Pharmacol. 2017;57(4):417–21.

    Article  PubMed  CAS  Google Scholar 

  219. Darwich AS, Ogungbenro K, Vinks AA, et al. Why has model-informed precision dosing not yet become common clinical reality? lessons from the past and a roadmap for the future. Clin Pharmacol Ther. 2017;101(5):646–56.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, University of Geneva, Geneva, Switzerland

    Flavia Storelli, Caroline Samer, Jules Desmeules & Youssef Daali

  2. Geneva-Lausanne School of Pharmacy, University of Geneva, Geneva, Switzerland

    Flavia Storelli, Jules Desmeules & Youssef Daali

  3. Faculty of Medicine, University of Geneva, Geneva, Switzerland

    Caroline Samer, Jean-Luc Reny, Jules Desmeules & Youssef Daali

  4. Swiss Center for Applied Human Toxicology, Geneva, Switzerland

    Caroline Samer, Jules Desmeules & Youssef Daali

  5. Department of Internal Medicine, Rehabilitation and Geriatrics, Geneva University Hospitals, University of Geneva, Geneva, Switzerland

    Jean-Luc Reny

Authors
  1. Flavia Storelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Caroline Samer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jean-Luc Reny
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jules Desmeules
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Youssef Daali
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Youssef Daali.

Ethics declarations

Funding

No funding was received for the preparation of this manuscript.

Conflict of interest

Flavia Storelli, Caroline Samer, Jean-Luc Reny, Jules Desmeules and Youssef Daali declare no conflicts of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 18 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Storelli, F., Samer, C., Reny, JL. et al. Complex Drug–Drug–Gene–Disease Interactions Involving Cytochromes P450: Systematic Review of Published Case Reports and Clinical Perspectives. Clin Pharmacokinet 57, 1267–1293 (2018). https://doi.org/10.1007/s40262-018-0650-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-018-0650-9

Search

Navigation