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.
Footnotes
This work was supported by the National Institutes of Health National Center for Research Resources [Grant S10-RR023461, Award KL2-RR024154] (to S.M.P. and P.E.E., respectively); the National Institutes of Health National Institute of General Medical Sciences [Grant R01-GM073031] (to S.M.P.); and the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS30318] (to P.M.K.).
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.040642.
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ABBREVIATIONS:
- CA
- cardiac arrest
- PK
- pharmacokinetic
- P450
- cytochrome P450
- PaCO2
- partial pressure of carbon dioxide
- MAP
- mean arterial pressure
- BUN
- blood urea nitrogen
- UPLC
- ultraperformance liquid chromatography
- AUC
- area under the curve
- OFV
- objective function value
- ANOVA
- analysis of variance.
- Received May 16, 2011.
- Accepted August 25, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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