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

Content Provider	Europe PMC
Author	Zhou, Jiangquan Empey, Philip E. Bies, Robert R. Kochanek, Patrick M. Poloyac, Samuel M.
Copyright Year	2011
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 (V1), dextromethorphan (V1), and peripheral compartment for chlorzoxazone (V2) (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.
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ISSN	00909556
Volume Number	39
DOI	10.1124/dmd.111.040642
PubMed Central reference number	PMC3226379
Issue Number	12
PubMed reference number	21868471
Journal	Drug Metabolism and Disposition [Drug Metab Dispos]
e-ISSN	1521009X
Language	English
Publisher	The American Society for Pharmacology and Experimental Therapeutics
Publisher Date	2011-08-25
Access Restriction	Open
Rights License	Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
Content Type	Text
Resource Type	Article
Subject	Pharmacology Pharmaceutical Science