RT Journal Article
SR Electronic
T1 Cardiac Arrest and Therapeutic Hypothermia Interaction with Isoform-specific Cytochrome P450 Drug Metabolism
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.111.040642
DO 10.1124/dmd.111.040642
A1 Jiangquan Zhou
A1 Philip E. Empey
A1 Robert R. Bies
A1 Patrick M. Kochanek
A1 Samuel M. Poloyac
YR 2011
UL http://dmd.aspetjournals.org/content/early/2011/08/25/dmd.111.040642.abstract
AB Mild therapeutic hypothermia is emerging clinically as a neuroprotection therapy for cardiac arrest (CA) victims, however its effects combined with the pathogenesis of critical illness 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 (PK) of their probe drugs as a function of altered body temperature. Animals were randomized into sham normothermia (37.5-38°C), sham hypothermia (32.5-33°C), CA normothermia, and CA hypothermia groups. Probe drugs (midazolam, diclofenac, dextromethorphan and chlorzoxazone) were given simultaneously by IV bolus after temperature stabilization. Multiple blood samples were collected between 0-8 hours after drug administration. PK analysis was conducted using a non-compartmental approach and population PK modelling. Non-compartmental analysis showed that the clearance of midazolam (CYP3A) in CA hypothermia was reduced from sham normothermia (681.6±190.0 mL/hr/kg vs 1268.8±348.9 mL/hr/kg, p<0.05). The clearance of chlorzoxazone (CYP2E) in CA hypothermia was reduced from sham normothermia (229.6±75.6 mL/hr/kg vs 561.89±215.9 mL/hr/kg, p<0.05). Population PK analysis 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 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 indicated that hypothermia, CA and interaction lead to CYP isoform specific alteration in activities and magnitudes in drug metabolism and disposition.