Using drug probes to monitor hepatic drug metabolism in critically ill patients: midazolam, a flawed but useful tool for clinical investigation of CYP3A activity?

Importance of the field: In the UK, acute kidney injury (AKI) occurs in 25% of patients admitted to intensive care. Outcome is worsened in the presence of AKI for reasons not easily explained. AKI unpredictably affects the pharmacokinetics and pharmacodynamics of drugs and dosing in patients with AKI is largely based on data from chronic kidney disease patients, but how appropriately is unknown. Areas covered in this review: Midazolam as a drug probe of CYP3A activity is reviewed, with discussion of its limitations and alternatives in critically ill patients. Pharmacogenetics of CYP3A enzymes and their significance are discussed and emerging evidence that AKI affects liver metabolism is reviewed. What the reader will gain: The aim is to give the reader insight into the complexities of in vivo research in critically ill patient with discussion of interaction between the kidney and liver. We explain the use of midazolam as a drug probe for the investigation of the effect of AKI on hepatic function. Take home message: Critically ill patients are difficult to manage but methods are now available for investigation of complex interrelationships that complicate the care and management of these patients with the potential to improve safety, efficacy and outcome, particularly for drug administration.