Therapeutic hypothermia-induced pharmacokinetic alterations on CYP2E1 chlorzoxazone-mediated metabolism in a cardiac arrest rat model.
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.[1]References
- Therapeutic hypothermia-induced pharmacokinetic alterations on CYP2E1 chlorzoxazone-mediated metabolism in a cardiac arrest rat model. Tortorici, M.A., Kochanek, P.M., Bies, R.R., Poloyac, S.M. Crit. Care Med. (2006) [Pubmed]
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