Cardiac arrest and therapeutic hypothermia decrease isoform-specific cytochrome p450 drug metabolism

Jiangquan Zhou, Philip E. Empey, Robert Bies, Patrick M. Kochanek, Samuel M. Poloyac

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)2209-2218
Number of pages10
JournalDrug Metabolism and Disposition
Volume39
Issue number12
DOIs
StatePublished - Dec 2011

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Induced Hypothermia
Heart Arrest
Cytochrome P-450 Enzyme System
Protein Isoforms
Hypothermia
Chlorzoxazone
Midazolam
Pharmaceutical Preparations
Cytochrome P-450 CYP3A
Pharmacokinetics
Dextromethorphan
Cytochrome P-450 CYP2E1
Diclofenac
Wounds and Injuries
Body Temperature
Population
Temperature

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Cardiac arrest and therapeutic hypothermia decrease isoform-specific cytochrome p450 drug metabolism. / Zhou, Jiangquan; Empey, Philip E.; Bies, Robert; Kochanek, Patrick M.; Poloyac, Samuel M.

In: Drug Metabolism and Disposition, Vol. 39, No. 12, 12.2011, p. 2209-2218.

Research output: Contribution to journalArticle

Zhou, Jiangquan ; Empey, Philip E. ; Bies, Robert ; Kochanek, Patrick M. ; Poloyac, Samuel M. / Cardiac arrest and therapeutic hypothermia decrease isoform-specific cytochrome p450 drug metabolism. In: Drug Metabolism and Disposition. 2011 ; Vol. 39, No. 12. pp. 2209-2218.
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