Using midazolam to monitor changes in hepatic drug metabolism in critically ill patients.
OBJECTIVE
Critical illness and associated sequelae can cause severe metabolic disturbances. The effects these have on hepatic drug metabolism are poorly understood. In vivo, enzyme specific drug probes are used to measure changes in hepatic drug metabolism but they require multiple blood sampling and are time consuming. We suggest that a single measurement, 4 h after intravenous administration of midazolam is a reliable indicator of integral plasma midazolam exposure or area under the curve (AUC) in critically ill patients. We also explore the hypothesis that acute kidney injury (AKI) directly impairs hepatic metabolism of drugs in critically ill patients.


METHODS
A prospective study in 20 critically ill patients who were not taking specific enzyme inhibitors or inducers or benzodiazepines. Correlation between 4 h midazolam concentration and AUC was calculated. We also assessed the difference in metabolism between the patients with normal renal function and those with AKI.


RESULTS
Four hour midazolam concentration correlated with AUC r = 0.956 (p < 0.0001). In addition, the 4 h midazolam concentration was greater in critically ill patients with AKI than those with normal renal function p = 0.023.


CONCLUSIONS
A single-time-point determination of plasma midazolam concentration is a reliable predictor of integral plasma midazolam exposure in critically ill patients. This tool can now be used to assess the effects of critical illness on hepatic drug metabolism. Using this method, we suggest that AKI reduces the hepatic metabolism of midazolam in critically ill patients.
Kirwan
Christopher John
CJ
General Intensive Care, St George's University of London, St Georges Hospital Blackshaw Road, London, SW17 0QT, UK. cjkirwan100@msn.com
Lee
Terry
T
Holt
David W
DW
Grounds
R Michael
RM
MacPhee
Iain A M
IA
Philips
Barbara J
BJ
D058186:Acute Kidney Injury / Q000150:complications; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D016638:Critical Illness; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000097:blood / Q000378:metabolism; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000378:metabolism*; D008875:Middle Aged; D011446:Prospective Studies
D006993:Hypnotics and Sedatives; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam