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

Critical Care Medicine
Michael A TortoriciSamuel M Poloyac

Abstract

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. Laboratory investigation. University pharmacy school and animal research facility. Sixteen male Sprague-Dawley rats. 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. Moderate hypothermia after cardiac arrest in rats markedly decreased the systemic clearance of the CYP2E1 substrate, chlorzoxazone...Continue Reading

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Citations

Mar 11, 2009·Journal of Neurotrauma·Patrick M KochanekSamuel A Tisherman
Dec 21, 2012·Pediatric Critical Care Medicine : a Journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies·Renée A ShellhaasVarsha Bhatt-Mehta
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Apr 9, 2011·Expert Opinion on Drug Metabolism & Toxicology·Jiangquan Zhou, Samuel M Poloyac
Apr 7, 2017·Therapeutic Advances in Drug Safety·Robert WitcherSandra L Kane-Gill

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