title: Mini-series: II. clinical aspects. clinically relevant CYP450-mediated drug interactions in the ICU.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacy, University Hospital Leuven, Herestraat 49, 3000, Louvain, Belgium, isabel.spriet@uz.kuleuven.ac.be.
authors.forename: Isabel
authors.initials: I
authors.lastname: Spriet
authors.forename: Wouter
authors.initials: W
authors.lastname: Meersseman
authors.forename: Jan
authors.initials: J
authors.lastname: de Hoon
authors.forename: Sandrina
authors.initials: S
authors.lastname: von Winckelmann
authors.forename: Alexander
authors.initials: A
authors.lastname: Wilmer
authors.forename: Ludo
authors.initials: L
authors.lastname: Willems
mesh_terms: D000208:Acute Disease; D000701:Analgesics, Opioid / Q000493:pharmacokinetics; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics; D000927:Anticonvulsants / Q000493:pharmacokinetics; D001569:Benzodiazepines / Q000493:pharmacokinetics; D002395:Catecholamines / Q000378:metabolism; D002908:Chronic Disease; D003422:Critical Care; D016572:Cyclosporine / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D016903:Drug Monitoring; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics; D007362:Intensive Care Units; D008874:Midazolam / Q000493:pharmacokinetics; D016559:Tacrolimus / Q000493:pharmacokinetics
chemical_list: D000701:Analgesics, Opioid; D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D002395:Catecholamines; D007166:Immunosuppressive Agents; D001569:Benzodiazepines; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam; D016559:Tacrolimus