Clinical use of systemic therapeutic hypothermia is being instituted nationally as standard of care for patients suffering a cardiac arrest (CA). Recent clinical trials have demonstrated the safety and neuroprotective benefits, thereby, prompting the American Heart Association to designate systemic hypothermia as a level one therapy in CA patients. In addition, hypothermia provides neuroprotective benefits after traumatic brain injury (TBI). Patients who suffer a CA or TBI receive a wide array of drugs that depend on hepatic metabolism by the cytochrome P450 (CYP450) enzyme system. In fact, several studies have demonstrated that hypothermia increases the plasma concentrations of hepatically eliminated drugs. Despite the increased clinical implementation and the potential for therapy-drug interaction, a paucity of data exists concerning the effects of therapeutic hypothermia on CYP450-mediated drug clearance. The hypotheses of this proposal are that: 1) Mild and moderate hypothermia differentially affect the in vitro functional activity and regulation of the 7 major CYP450 isoforms in rat CA and TBI models. 2) Mild to moderate hypothermia produce alterations in hepatic blood flow, intrinsic enzyme clearance, and plasma protein binding in rat CA and TBI models. 3) Mild and moderate hypothermia alters the disposition of therapeutic agents in vivo in rat CA and TBI models, thereby, affecting the full neuroprotective benefits of therapeutic hypothermia. This project will utilize combinations of in vivo pharmacokinetic assessments, in vitro functional regulation analyses, and analytical chemistry techniques in models of CA and TBI under normothermic (37 degrees), mild hypothermic (33 degrees), and moderately hypothermic (30 degrees) conditions. In addition, this research will lend insight into the cellular mechanisms that produce both acute and chronic changes in CYP450 function. The results of this research are necessary to determine: 1) The implications of hypothermic therapy after traumatic insult on the disposition of drugs that depend on hepatic elimination;2) The in vivo mechanism(s) by which hypothermia and trauma alter hepatic drug elimination, and;3) The effect of hypothermia and trauma on the cellular mechanisms and functional regulation of CYP450 isoform expression. Once completed, this research will provide critical information to design future clinical studies to optimize the benefits of this breakthrough therapy.
Showing the most recent 10 out of 11 publications
