title: Mild hypothermia decreases fentanyl and midazolam steady-state clearance in a rat model of cardiac arrest.
abstract: OBJECTIVE
  Therapeutic hypothermia is widely employed for neuroprotection after cardiac arrest. However, concern regarding elevated drug concentrations during hypothermia and increased adverse drug reaction risk complicates concurrent pharmacotherapy. Many commonly used medications in critically ill patients rely on the cytochrome P450 3A isoform for their elimination. Therefore, our study objectives were to determine the effect of mild hypothermia on the in vivo pharmacokinetics of fentanyl and midazolam, two clinically relevant cytochrome P450 3A substrates, after cardiac arrest and to investigate the mechanisms of these alterations.
  
  
  METHODS
  Prospective, randomized, controlled study.
  
  
  METHODS
  University research laboratory.
  
  
  METHODS
  Thirty-two adult male Sprague-Dawley rats.
  
  
  METHODS
  An asphyxial cardiac arrest rat model was used and mild hypothermia (33°C) was induced 1 hr post injury by surface cooling and continued for 10 hrs to mimic the prolonged clinical application of hypothermia accompanied by intensive care interventions. Fentanyl and midazolam were independently administered by intravenous infusion and plasma and brain concentrations were analyzed using ultraperformance liquid chromatography tandem mass spectrometry. Cytochrome P450 3a2 protein expression was measured and a Michaelis-Menten enzyme kinetic analysis was performed at 37°C and 33°C using control rat microsomes.
  
  
  RESULTS
  Mild hypothermia decreased the systemic clearance of both fentanyl (61.5 ± 11.5 to 48.9 ± 8.95 mL/min/kg; p < .05) and midazolam (89.2 ± 12.5 to 73.6 ± 12.1 mL/min/kg; p < .05) after cardiac arrest. The elevated systemic concentrations did not lead to parallel increased brain exposures of either drug. Mechanistically, no differences in cytochrome P450 3a2 expression was observed, but the in vitro metabolism of both drugs was decreased at 33°C vs. 37°C through reductions in enzyme metabolic capacity rather than substrate affinity.
  
  
  CONCLUSIONS
  Mild hypothermia reduces the systemic clearances of fentanyl and midazolam in rats after cardiac arrest through alterations in cytochrome P450 3a2 metabolic capacity rather than enzyme affinity as observed with other cytochrome P450s. Contrasting effects on blood and brain levels further complicates drug dosing. Consideration of the impact of hypothermia on medications whose clearance is dependent on P450 3A metabolism is warranted.
authors: Department of Pharmacy and Therapeutics, School of Medicine, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA.
authors: Philip E
authors: PE
authors: Empey
authors: Tricia M
authors: TM
authors: Miller
authors: Ashley H
authors: AH
authors: Philbrick
authors: John A
authors: JA
authors: Melick
authors: Patrick M
authors: PM
authors: Kochanek
authors: Samuel M
authors: SM
authors: Poloyac
mesh_terms: D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004195:Disease Models, Animal; D005283:Fentanyl / Q000097:blood / Q000493:pharmacokinetics*; D006323:Heart Arrest / Q000378:metabolism / Q000628:therapy*; D006993:Hypnotics and Sedatives / Q000097:blood / Q000493:pharmacokinetics*; D007036:Hypothermia, Induced; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D008874:Midazolam / Q000097:blood / Q000494:pharmacology*; D009294:Narcotics / Q000097:blood / Q000493:pharmacokinetics*; D010456:Peptides, Cyclic; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D006993:Hypnotics and Sedatives; D009294:Narcotics; D010456:Peptides, Cyclic; C074972:westiellamide; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam; D005283:Fentanyl