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

Abstract

OBJECTIVES:

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.

• Authors: Michael A Tortorici, Patrick M Kochanek, Robert R Bies, Samuel M Poloyac
• Journal: Critical care medicine (Crit Care Med) Vol. 34 Issue 3 Pg. 785-91 (Mar 2006) ISSN: 0090-3493 [Print] United States
• PMID: 16521272 (Publication Type: Evaluation Study, 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