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. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM073031-02
Application #
7282574
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Okita, Richard T
Project Start
2006-09-01
Project End
2010-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
2
Fiscal Year
2007
Total Cost
$249,408
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Empey, Philip E; Velez de Mendizabal, Nieves; Bell, Michael J et al. (2013) Therapeutic hypothermia decreases phenytoin elimination in children with traumatic brain injury. Crit Care Med 41:2379-87
Thampatty, Bhavani P; Klamerus, Megan M; Oberly, Patrick J et al. (2013) Hypothermia decreases cerebrospinal fluid asymmetric dimethylarginine levels in children with traumatic brain injury. Pediatr Crit Care Med 14:403-12
Poloyac, Samuel M; Empey, Philip E (2013) Drug dosing during hypothermia: to adjust, or not to adjust, that is the question. Pediatr Crit Care Med 14:228-9
Empey, Philip E; Miller, Tricia M; Philbrick, Ashley H et al. (2012) Mild hypothermia decreases fentanyl and midazolam steady-state clearance in a rat model of cardiac arrest. Crit Care Med 40:1221-8
Zhou, Jiangquan; Empey, Philip E; Bies, Robert R et al. (2011) Cardiac arrest and therapeutic hypothermia decrease isoform-specific cytochrome P450 drug metabolism. Drug Metab Dispos 39:2209-18
Zhou, Jiangquan; Poloyac, Samuel M (2011) The effect of therapeutic hypothermia on drug metabolism and response: cellular mechanisms to organ function. Expert Opin Drug Metab Toxicol 7:803-16
Hostler, David; Zhou, Jiangquan; Tortorici, Michael A et al. (2010) Mild hypothermia alters midazolam pharmacokinetics in normal healthy volunteers. Drug Metab Dispos 38:781-8
Salonia, Rosanne; Empey, Philip E; Poloyac, Samuel M et al. (2010) Endothelin-1 is increased in cerebrospinal fluid and associated with unfavorable outcomes in children after severe traumatic brain injury. J Neurotrauma 27:1819-25
Miller, Tricia M; Donnelly, Mark K; Crago, Elizabeth A et al. (2009) Rapid, simultaneous quantitation of mono and dioxygenated metabolites of arachidonic acid in human CSF and rat brain. J Chromatogr B Analyt Technol Biomed Life Sci 877:3991-4000
Tortorici, Michael A; Mu, Ying; Kochanek, Patrick M et al. (2009) Moderate hypothermia prevents cardiac arrest-mediated suppression of drug metabolism and induction of interleukin-6 in rats. Crit Care Med 37:263-9

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