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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Kirwan
Chris
C
SpR in Renal Medicine, St George's University of London, St George's Healthcare NHS Trust, Rm 30 1st floor Jenner Wing, London, UK.
MacPhee
Iain
I
Philips
Barbara
B
D058186:Acute Kidney Injury / Q000150:complications / Q000378:metabolism; D000818:Animals; D016638:Critical Illness; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008874:Midazolam / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics
C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam