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

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.