TY - JOUR T1 - Cardiac Arrest and Therapeutic Hypothermia Decrease Isoform-Specific Cytochrome P450 Drug Metabolism JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 2209 LP - 2218 DO - 10.1124/dmd.111.040642 VL - 39 IS - 12 AU - Jiangquan Zhou AU - Philip E. Empey AU - Robert R. Bies AU - Patrick M. Kochanek AU - Samuel M. Poloyac Y1 - 2011/12/01 UR - http://dmd.aspetjournals.org/content/39/12/2209.abstract N2 - 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. ER -