title: 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA 15261, USA.
authors.forename: Jiangquan
authors.initials: J
authors.lastname: Zhou
authors.forename: Philip E
authors.initials: PE
authors.lastname: Empey
authors.forename: Robert R
authors.initials: RR
authors.lastname: Bies
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kochanek
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Poloyac
mesh_terms: D000818:Animals; D001831:Body Temperature; D002853:Chromatography, Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006323:Heart Arrest / Q000201:enzymology / Q000628:therapy*; D007036:Hypothermia, Induced; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D010599:Pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System