Intensive Care Medicine

, Volume 35, Issue 4, pp 603–612 | Cite as

Mini-series: II. Clinical aspects. Clinically relevant CYP450-mediated drug interactions in the ICU

  • Isabel Spriet
  • Wouter Meersseman
  • Jan de Hoon
  • Sandrina von Winckelmann
  • Alexander Wilmer
  • Ludo Willems
Mini Series: Basic research-related topics in ICM



In the critically ill, multiple drug therapies for acute and chronic conditions are often used at the same time and adverse drug events occur frequently. Many pharmacological and disease-related factors, e.g. altered renal and hepatic function, catecholamine-related circulatory changes, altered drug volume of distribution, enteral versus parenteral feeding and morbid obesity, along with concomitant multiple drug regimens may account for the wide inter-individual variability in drug exposure and response in critically ill patients and for the high risk for drug–drug interactions to occur. The practicing intensivist must remain aware of the major mechanisms for drug–drug interactions, among which the drug-metabolizing enzyme inhibitory or induction potential of associated chemical entities are paramount. Metabolism-based drug–drug interactions are largely due to changes in levels of drug-metabolizing enzymes caused by one drug, leading to changes in the systemic exposure clearance of another. Among the numerous drug-metabolizing enzymes identified to date, the activity of cytochrome P450s (CYP450) is a critical determinant of drug clearance and appears to be involved in the mechanism of numerous clinically relevant drug–drug interactions observed in critically ill patients.


This manuscript will cover a practical overview of clinically relevant CYP450-mediated drug–drug interactions. Medications frequently used in the intensive care unit such as benzodiazepines, immunosuppressive agents, opioid analgesics, certain anticonvulsants, the azoles and macrolides have the potential to interact with CYP450-mediated metabolism and may lead to toxicity or therapeutic failure.


Drug–drug interactions CYP450 Inhibition Induction ICU 


  1. 1.
    Kopp BJ, Erstad BL, Allen ME, Theodorou AA, Priestley G (2006) Medication errors and adverse drug events in an intensive care unit: direct observation approach for detection. Crit Care Med 34:415–425PubMedCrossRefGoogle Scholar
  2. 2.
    Krishnan V, Murray P (2003) Pharmacologic issues in the critically ill. Clin Chest Med 24:671–688PubMedCrossRefGoogle Scholar
  3. 3.
    Baxter K, Stockley IH (2006) Stockley’s drug interactions, 7th edn. Pharmaceutical Press, LondonGoogle Scholar
  4. 4.
    Leape LL, Cullen DJ, Dempsey Clapp M, Burdick E, Demonaco HJ, Ives Erickson J, Bates DW (1999) Pharmacist participation on physician rounds and adverse drug events in the intensive care unit. JAMA 281:267–270CrossRefGoogle Scholar
  5. 5.
    Rivkin A (2007) Admission to a medical intensive care unit related to adverse drug reactions. Am J Health Syst Pharm 64:1840–1843PubMedCrossRefGoogle Scholar
  6. 6.
    Ellenhorn MJ, Sternad FA (1996) Problems of drug interactions. J Am Pharmacol Assoc NS 6:62–68Google Scholar
  7. 7.
    Pirmohamed M, Park BK (2003) Cytochrome P450 enzyme polymorphisms and adverse drug reactions. Toxicol 192:23–32CrossRefGoogle Scholar
  8. 8.
    Mann HJ (2006) Drug-associated disease: cytochrome P450 interactions. Crit Care Clin 22:329–345PubMedCrossRefGoogle Scholar
  9. 9.
    Wilkinson GR (2005) Drug metabolism and variability among patients in drug response. N Engl J Med 352:2211–2221PubMedCrossRefGoogle Scholar
  10. 10.
    Lewis DF (2004) 57 varieties: the human cytochromes P450. Pharmacogenom 5:305–318CrossRefGoogle Scholar
  11. 11.
    Lin JH, Lu AYH (1998) Inhibition and induction of cytochrome P450 and the clinical implications. Clin Pharmacokinet 35:361–390PubMedCrossRefGoogle Scholar
  12. 12.
    Kulmatycki KM, Jamali F (2005) Drug disease interactions: role of inflammatory mediators in disease and variability in drug response. J Pharm Pharmaceut Sci 8:602–625Google Scholar
  13. 13.
    Renton KW (2004) Cytochrome P450 regulation and drug biotransformation during inflammation and infection. Curr Drug Metab 5:235–243PubMedCrossRefGoogle Scholar
  14. 14.
    Venkatakrishnan K, von Moltke LL, Greenblatt DJ (2000) Effects of the antifungal agents on oxidative drug metabolism. Clin Pharmacokinet 38:111–180PubMedCrossRefGoogle Scholar
  15. 15.
    Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivistö KT (2003) Pharmacokinetic interactions with rifampicin. Clinical relevance. Clin Pharmacokinet 42:819–850PubMedCrossRefGoogle Scholar
  16. 16.
    Finch CK, Chrisman CR, Baciewicz AM, Self TH (2002) Rifampin and rifabutin drug interactions. An update. Arch Intern Med 162:985–992PubMedCrossRefGoogle Scholar
  17. 17.
    Gerson LB, Triadafilopoulos G (2001) Proton pump inhibitors and their drug interactions: an evidence-based approach. Eur J Gastroenterol Hepatol 13:611–616PubMedCrossRefGoogle Scholar
  18. 18.
    Czock D, Keller F, Rasche FM, Häussler U (2005) Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids. Clin Pharmacokinet 44:61–98PubMedCrossRefGoogle Scholar
  19. 19.
    Tanaka E (1999) Clinically significant pharmacokinetic drug interactions between anti-epileptic drugs. J Clin Pharm Ther 24:87–89PubMedCrossRefGoogle Scholar
  20. 20.
    Perucca E (2005) Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol 61:246–255CrossRefGoogle Scholar
  21. 21.
    Pai MP, Momary KM, Rodvold KA (2006) Antibiotic drug interactions. Med Clin N Am 90:1223–1255PubMedCrossRefGoogle Scholar
  22. 22.
    Saad AH, DePestel D, Carver P (2006) Factors influencing the magnitude and clinical significance of drug interactions between azole antifungals and select immunosuppressants. Pharmacotherapy 26:1730–1744PubMedCrossRefGoogle Scholar
  23. 23.
    Cozza KL, Armstrong SC, Oesterheld JR (2003) Concise guide to drug interaction principles for medical practice, 2nd edn. American Psychiatric Publishing, Washington, DCGoogle Scholar
  24. 24.
    Dresser GK, Spence JD, Bailey DG (2000) Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet 38:41–57PubMedCrossRefGoogle Scholar
  25. 25.
    Doherty MM, Charman WH (2002) The mucosa of the small intestine: how clinically relevant as an organ of drug metabolism. Clin Pharmacokinet 41:235–253PubMedCrossRefGoogle Scholar
  26. 26.
    Backman JT, Kivistö KT, Olkkola KT, Neuvonen PJ (1998) The area under the plasma concentration-time curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin. Eur J Clin Pharmacol 54:53–58PubMedCrossRefGoogle Scholar
  27. 27.
    Olkkola KT, Ahonen J, Neuvonen PJ (1996) The effects of the systemic antimycotics, itraconazole and fluconazole, on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam. Anesth Analg 82:511–516PubMedCrossRefGoogle Scholar
  28. 28.
    Theuretzbacher U, Ihle F, Derendorf H (2006) Pharmacokinetic/pharmacodynamic profile of voriconazole. Clin Pharmacokinet 45:649–663PubMedCrossRefGoogle Scholar
  29. 29.
    Gorski JC, Jones DR, Haehner-Daniels BD, Hamman MA, O’Mara EM, Hall SD (1998) The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin. Clin Pharmacol Ther 64:133–143PubMedCrossRefGoogle Scholar
  30. 30.
    Yeates RA, Laufen H, Zimmermann T (1996) Interaction between midazolam and clarithromycin: comparison with azithromycin. Int J Clin Pharmacol Ther 34:400–405PubMedGoogle Scholar
  31. 31.
    Ahonen J, Olkkola KT, Takala A, Neuvonen PJ (1999) Interaction between fluconazole and midazolam in intensive care patients. Acta Anaesthesiol Scand 43:509–514PubMedCrossRefGoogle Scholar
  32. 32.
    Backman JT, Olkolla KT, Ojala M, Laaksovirta H, Neuvonen PJ (1996) Concentrations and effects of oral midazolam are greatly reduced in patients treated with carbamazepine or phenytoin. Epilepsia 37:253–257PubMedCrossRefGoogle Scholar
  33. 33.
    Backman JT, Olkkola KT, Neuvonen PJ (1996) Rifampin drastically reduces plasma concentrations and effects of oral midazolam. Clin Pharmacol Ther 59:7–13PubMedCrossRefGoogle Scholar
  34. 34.
    Kress JP, Pohlman AS, O’Connor MF, Hall JB (2000) Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 342:1471–1477PubMedCrossRefGoogle Scholar
  35. 35.
    Leather HL (2004) Drug interactions in the hematopoetic stem cell transplant (HSCT) recipient: what every transplanter needs to know. Bone Marr Transplant 33:137–152CrossRefGoogle Scholar
  36. 36.
    Christians U, Jacobsen W, Benet LZ, Lampen A (2002) Mechanisms of clinically relevant drug interactions associated with tacrolimus. Clin Pharmacokinet 41:813–851PubMedCrossRefGoogle Scholar
  37. 37.
    Ibrahim RB, Abella EM, Chandrasekar PH (2002) Tacrolimus-clarithromycin interaction in a patient receiving bone marrow transplantation. Ann Pharmacother 36:1971–1972PubMedCrossRefGoogle Scholar
  38. 38.
    Jensen C, Jordan M, Shapiro R, Scantlebury V, Hakala T, Fung J, Starzl T, Venkataramanan R (1994) Interaction between tacrolimus and erythromycin. Lancet 344:825PubMedCrossRefGoogle Scholar
  39. 39.
    Paterson DL, Singh N (1997) Interactions between tacrolimus and antimicrobial agents. Clin Infect Dis 25:1430–1440PubMedCrossRefGoogle Scholar
  40. 40.
    Vfend (voriconazole) package insert. Pfizer Inc. January 2006Google Scholar
  41. 41.
    Romero AJ, Pogamp PL, Nilsson LG, Wood N (2002) Effect of voriconazole on the pharmacokinetics of cyclosporine in renal transplant patients. Clin Pharmacol Ther 71:226–234PubMedCrossRefGoogle Scholar
  42. 42.
    Canafax DM, Graves NM, Hilligoss DM, Carleton BC, Gardner MJ, Matas AJ (1991) Interaction between cyclosporine and fluconazole in renal allograft recipients. Transplantation 51:1014–1018PubMedCrossRefGoogle Scholar
  43. 43.
    Aguado JM, Herrero JA, Gavalda J, Torre-Cisneros J, Blanes M, Rufi G, Moreno A, Gurgui A, Hayek M, Lumbreras C, and the Spanish Transplantation Infection Study Group, GESITRA (1997) Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in Spain. Transplantation 63:1276–1286CrossRefGoogle Scholar
  44. 44.
    Karasu Z, Gurakar A, Carlson J, Pennington S, Kerwin B, Wright H, Nour B, Sebastian A (2001) Acute tacrolimus overdose and treatment with phenytoin in liver transplant recipients. J Okla State Med Assoc 94:121–123PubMedGoogle Scholar
  45. 45.
    McLaughlin GE, Gonzalez-Rossique M, Gelman B, Kato T (2000) Use of phenobarbital in the management of acute tacrolimus toxicity: a case report. Transplant Proc 32:665–668PubMedCrossRefGoogle Scholar
  46. 46.
    Armstrong SC, Cozza KL (2003) Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality, Part I. Psychosomatics 44:167–171PubMedCrossRefGoogle Scholar
  47. 47.
    Armstrong SC, Cozza L (2003) Pharmacokinetic drug interactions of morphine, codeine and their derivatives: theory and clinical reality, Part II. Psychosomatics 44:515–520PubMedCrossRefGoogle Scholar
  48. 48.
    Buck ML, Blumer JL (1991) Opioids and other analgesics. Adverse effects in the intensive care unit. Crit Care Clin 7:615–637PubMedGoogle Scholar
  49. 49.
    Palkama VJ, Neuvonen PJ, Olkolla KT (1998) The CYP3A4 inhibitor itraconazole has no effect on the pharmacokinetics and pharmacodynamics of i.v. fentanyl. Br J Anaesth 81:598–600PubMedGoogle Scholar
  50. 50.
    Tempelhoff R, Modica P, Spitznagel E (1988) Increased fentanyl requirement in patients receiving long-term anticonvulsant therapy. Anesthesiology 69:A594CrossRefGoogle Scholar
  51. 51.
    Beers R, Camporesi E (2004) Remifentanil update: clinical science and utility. CNS Drugs 18:1085–1104PubMedCrossRefGoogle Scholar
  52. 52.
    Linthoudt H, Van Raemdonck D, Lerut T, Demedts M, Verleden G (1996) The association of itraconazole and methylprednisolone may give rise to important steroid-related side effects. J Heart Lung Transplant 15:1165PubMedGoogle Scholar
  53. 53.
    Bartoszek M, Brenner AM, Szefler SJ (1987) Prednisolone and methylprednisolone kinetics in children receiving anticonvulsant therapy. Clin Pharmacol Ther 42:424–432PubMedGoogle Scholar
  54. 54.
    Ray WA, Murray KT, Meredith S, Narasimhulu SS, Hall K, Stein CM (2004) Oral erythromycin and the risk of sudden death from cardiac causes. N Engl J Med 351:1089–1096PubMedCrossRefGoogle Scholar
  55. 55.
    Liu BA, Juurlink DN (2004) Drug and the QT interval—Caveat Doctor. N Engl J Med 351:1053–1056PubMedCrossRefGoogle Scholar
  56. 56.
    Wallace RJ, Brown BA, Griffith DE, Girard W, Tanaka K (1995) Reduced serum levels of clarithromycin in patients treated with multidrug regimens including rifampin or rifabutin for Mycobacterium avium–M. intracellulare infection. J Infect Dis 171:747–750PubMedGoogle Scholar
  57. 57.
    Telt S, Carey D, Lee HS (1992) Drug interactions with fluconazole. Med J Aust 156:365Google Scholar
  58. 58.
    Blum RA, Wilton JH, Hilligoss DM, Gardner MJ, Henry EB, Harrisson NJ, Schentag JJ (1991) Effect of fluconazole on the disposition of phenytoin. Clin Pharmacol Ther 49:420–425PubMedGoogle Scholar
  59. 59.
    Flockhart DA, Tanus-Santos JE (2002) Implications of cytochrome P450 interactions when prescribing medication for hypertension. Arch Intern Med 162:405–412PubMedCrossRefGoogle Scholar
  60. 60.
    Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. 1 December 2007. Developed by the DHHS Panel on antiretroviral guidelines for adults and adolescents—a working group of the office of AIDS research advisory council (OARAC). Available from: Accessed on: 15 January 2008
  61. 61.
    Burger DM, Meenhorst PL, Mulder JW, Kraaijeveld CL, Koks CHW, Bult A, Bijnen JH (1994) Therapeutic drug monitoring of phenytoin in patients with the acquired immunodeficiency syndrome. Ther Drug Monit 16:616–620PubMedCrossRefGoogle Scholar
  62. 62.
    Blyden GT, Scavone JM, Greenblatt DJ (1988) Metronidazole impairs clearance of phenytoin but not of alprazolam or lorazepam. J Clin Pharmacol 28:240–245PubMedGoogle Scholar
  63. 63.
    Kay L, Kampmann JP, Svendsen TL, Vergman B, Hansen JEM, Skovsted L, Kristenen M (1985) Influence of rifampicin and isoniazid on the kinetics of phenytoin. Br J Clin Pharmacol 20:323–326PubMedGoogle Scholar
  64. 64.
    Holbrook AM, Pereira JA, Labiris R, Mc Donald H, Douketis JD, Crowther M, Wells PS (2005) Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 165:1095–1106PubMedCrossRefGoogle Scholar
  65. 65.
    Budnitz DS, Shehab N, Kegler SR, Richards CL (2007) Medication use leading to emergency department visits for adverse drug events in older adults. Ann Intern Med 147:755–765PubMedGoogle Scholar
  66. 66.
    Limdi NA, Veenstra DL (2008) Warfarin pharmacogenetics. Pharmacother 28:1084–1087CrossRefGoogle Scholar
  67. 67.
    Schwarz UI, Ritchie MD, Bradford Y, Li C, Dudek SM, Frye-Anderson A, Kim RB, Roden DM, Stein CM (2008) Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med 358:999–1008PubMedCrossRefGoogle Scholar
  68. 68.
    US Food and Drug Administration. Warfarin product labelling. Available from Accessed 1 September 2008
  69. 69.
    Ozawa S, Soyama A, Saeki M, Fukushima-Uesaka H, Itoda M, Koyano S, Sai K, Ohno Y, Saito Y, Sawada J (2004) Ethnic differences in genetic polymorphisms of CYP2D6, CYP2C19, CYP3As and MDR1/ABCB1. Drug Metab Pharmacokinet 19:83–95PubMedCrossRefGoogle Scholar
  70. 70.
    Stamer UM, Stüber F, Muders T, Musshoff F (2008) Respiratory depression with tramadol in a patient with renal impairment and CYP2D6 gene duplication. Anesth Analg 107:926–929PubMedCrossRefGoogle Scholar
  71. 71.
    Gashe Y, Daaili Y, Fathi M, Chiappe A, Cottini S, Dayer P, Desmeules J (2004) Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med 351:2827–2837CrossRefGoogle Scholar
  72. 72.
    Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder SJ (2006) Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine prescribed mother. Lancet 368:704PubMedCrossRefGoogle Scholar
  73. 73.
    Skop BP, Brown TM, Mareth TR (1995) The serotonin syndrome associated with paroxetine. Am J Emerg Med 13:606–607CrossRefGoogle Scholar
  74. 74.
    Kroon LA (2007) Drug interactions with smoking. Am J Health Syst Pharm 64:1917–1921PubMedCrossRefGoogle Scholar
  75. 75.
    Mouly S, Meune C, Bergmann JF (2007) Application and clinical value of in vitro models in predicting CYP-mediated drug–drug interactions in the ICU. I. Basic Science (accepted)Google Scholar
  76. 76.
    US Food and Drug Administration. Center for Devices and Radiological Health consumer information. New device clearance. Roche Amplichip cytochrome P450 genotyping test and Affymetrix GeneChip Microarray Instrumentation System—K042259. Available from: Accessed 16 September 2008

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Isabel Spriet
    • 1
  • Wouter Meersseman
    • 2
  • Jan de Hoon
    • 3
  • Sandrina von Winckelmann
    • 1
  • Alexander Wilmer
    • 2
  • Ludo Willems
    • 1
  1. 1.Department of PharmacyUniversity Hospital LeuvenLouvainBelgium
  2. 2.Medical Intensive Care UnitUniversity Hospital LeuvenLouvainBelgium
  3. 3.Centre for Clinical PharmacologyUniversity Hospital LeuvenLouvainBelgium

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