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Cardiac arrest and therapeutic hypothermia decrease isoform-specific cytochrome P450 drug metabolism.

Abstract
Mild therapeutic hypothermia is emerging clinically as a neuroprotection therapy for individuals experiencing cardiac arrest (CA); however, its effects combined with disease pathogenesis on drug disposition and response have not been fully elucidated. We determined the activities of four major hepatic-metabolizing enzymes (CYP3A, CYP2C, CYP2D, and CYP2E) during hypothermia after experimental CA in rats by evaluating the pharmacokinetics of their probe drugs as a function of altered body temperature. Animals were randomized into sham normothermia (37.5-38°C), CA normothermia, sham hypothermia (32.5-33°C), and CA hypothermia groups. Probe drugs (midazolam, diclofenac, dextromethorphan, and chlorzoxazone) were given simultaneously by intravenous bolus after temperature stabilization. Multiple blood samples were collected between 0 and 8 h after drug administration. Pharmacokinetic (PK) analysis was conducted using a noncompartmental approach and population PK modeling. Noncompartmental analysis showed that the clearance of midazolam (CYP3A) in CA hypothermia was reduced from sham normothermia rats (681.6 ± 190.0 versus 1268.8 ± 348.9 ml · h(-1) · kg(-1), p < 0.05). The clearance of chlorzoxazone (CYP2E) in CA hypothermia was also reduced from sham normothermia rats (229.6 ± 75.6 versus 561.89 ± 215.9 ml · h(-1) · kg(-1), p < 0.05). Population PK analysis further demonstrated the decreased clearance of midazolam (CYP3A) was associated with CA injury (p < 0.05). The decreased clearance of chlorzoxazone (CYP2E1) was also associated with CA injury (p < 0.01). Hypothermia was found to be associated with the decreased volume of distribution of midazolam (V(1)), dextromethorphan (V(1)), and peripheral compartment for chlorzoxazone (V(2)) (p < 0.05, p < 0.05, and p < 0.01, respectively). Our data indicate that hypothermia, CA, and their interaction alter cytochrome P450-isoform specific activities in an isoform-specific manner.
AuthorsJiangquan Zhou, Philip E Empey, Robert R Bies, Patrick M Kochanek, Samuel M Poloyac
JournalDrug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 39 Issue 12 Pg. 2209-18 (Dec 2011) ISSN: 1521-009X [Electronic] United States
PMID21868471 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Isoenzymes
  • Cytochrome P-450 Enzyme System
Topics
  • Animals
  • Body Temperature
  • Chromatography, Liquid
  • Cytochrome P-450 Enzyme System (metabolism)
  • Heart Arrest (enzymology, therapy)
  • Hypothermia, Induced
  • Isoenzymes (metabolism)
  • Male
  • Mass Spectrometry
  • Pharmacokinetics
  • Rats
  • Rats, Sprague-Dawley

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