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Cardiac arrest and therapeutic hypothermia decrease isoform-specific cytochrome P450 drug metabolism

Jiangquan Zhou1, Philip E Empey, Robert R Bies

  • 1Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA 15261, USA.

Drug Metabolism and Disposition: the Biological Fate of Chemicals
|August 27, 2011
PubMed

Insights

Mild therapeutic hypothermia and cardiac arrest (CA) alter drug metabolism. This study found that hypothermia and CA significantly reduce the activity of key drug-metabolizing enzymes, impacting drug disposition.

Area of Science:

  • Pharmacology
  • Toxicology
  • Physiology

Background:

  • Mild therapeutic hypothermia is a neuroprotection strategy after cardiac arrest (CA).
  • The combined effects of hypothermia and CA on drug metabolism are not fully understood.
  • Understanding these effects is crucial for optimizing drug therapy in post-CA patients.

Purpose of the Study:

  • To investigate the impact of hypothermia and CA on the activity of major hepatic drug-metabolizing enzymes.
  • To evaluate how these conditions alter the pharmacokinetics of probe drugs metabolized by CYP3A, CYP2C, CYP2D, and CYP2E enzymes.
  • To determine the specific effects of hypothermia, CA, and their interaction on drug disposition.

Main Methods:

  • Experimental study in rats subjected to sham normothermia, CA normothermia, sham hypothermia, and CA hypothermia.
  • Simultaneous intravenous administration of probe drugs: midazolam (CYP3A), diclofenac (CYP2C), dextromethorphan (CYP2D), and chlorzoxazone (CYP2E).
  • Pharmacokinetic (PK) analysis using noncompartmental and population PK modeling to assess drug clearance and volume of distribution.

Main Results:

  • CA hypothermia significantly reduced the clearance of midazolam (CYP3A) and chlorzoxazone (CYP2E) compared to sham normothermia.
  • Population PK analysis confirmed decreased midazolam and chlorzoxazone clearance associated with CA injury.
  • Hypothermia was linked to a decreased volume of distribution for midazolam, dextromethorphan, and chlorzoxazone.

Conclusions:

  • Hypothermia and cardiac arrest, individually and interactively, alter cytochrome P450 enzyme activities.
  • These alterations are isoform-specific, affecting drug disposition in a complex manner.
  • The findings highlight the need to consider hypothermia and CA when managing drug therapy in patients.

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