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Therapeutic hypothermia-induced pharmacokinetic alterations on CYP2E1 chlorzoxazone-mediated metabolism in a cardiac arrest rat model.

AbstractOBJECTIVES:
Therapeutic hypothermia has demonstrated considerable benefit in patients experiencing cardiac arrest. Despite increasing clinical use, there is a paucity of information regarding the effect of hypothermia on the disposition of medications, specifically cytochrome P450-mediated drug metabolism. The objective was to determine the effect of hypothermia after cardiac arrest on the in vivo kinetics of a cytochrome P450 (CYP2E1) probe drug, chlorzoxazone, and to investigate the mechanism of these alterations.
DESIGN:
Laboratory investigation.
SETTING:
University pharmacy school and animal research facility.
SUBJECTS:
Sixteen male Sprague-Dawley rats.
INTERVENTIONS:
An asphyxial arrest rat model was used and moderate hypothermia was induced immediately postinsult via surface cooling. Chlorzoxazone was administered as an intravenous bolus, and plasma concentrations were analyzed using high-performance liquid chromatography methods. Protein binding was analyzed using rat control plasma, and Michaelis-Menten enzyme kinetic analysis was performed at 37 degrees C and 30 degrees C using control rat microsomes at varying concentrations of chlorzoxazone.
MEASUREMENTS AND MAIN RESULTS:
Moderate hypothermia after cardiac arrest in rats markedly decreased the systemic clearance of the CYP2E1 substrate, chlorzoxazone, when compared with normothermia after cardiac arrest, 1.26+/-0.34 mL/min vs. 0.580+/-0.37 mL/min (p<.001). No changes in chlorzoxazone protein binding were observed at 37 degrees C and 30 degrees C, and CYP2E1 enzyme capacity (maximum velocity) was not altered at these different incubation temperatures. However, Michaelis-Menten constant was significantly increased at 30 degrees C (551+/-150 microM) compared with incubations at 37 degrees C (255+/-52 microM, p<.01).
CONCLUSIONS:
Moderate hypothermia markedly reduces the systemic clearance of chlorzoxazone in cardiac arrest rats. This results from hypothermia-induced decreases in the CYP2E1 enzyme affinity for the substrate chlorzoxazone. This is the first systematic mechanistic investigation of the effect of hypothermia on CYP2E1-mediated metabolism.
AuthorsMichael A Tortorici, Patrick M Kochanek, Robert R Bies, Samuel M Poloyac
JournalCritical care medicine (Crit Care Med) Vol. 34 Issue 3 Pg. 785-91 (Mar 2006) ISSN: 0090-3493 [Print] United States
PMID16521272 (Publication Type: Evaluation Studies, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Cytochrome P-450 CYP2E1
  • Chlorzoxazone
Topics
  • Analysis of Variance
  • Animals
  • Area Under Curve
  • Chlorzoxazone (pharmacokinetics)
  • Cytochrome P-450 CYP2E1 (metabolism, pharmacokinetics)
  • Heart Arrest (therapy)
  • Hypothermia, Induced
  • Male
  • Metabolic Clearance Rate
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley

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