Evaluation of the effects of therapeutic hypothermia and cardiac arrest on specific cytochrome P450 isoform activity
Abstract
Therapeutic hypothermia (TH, 32-35C) mediated neuroprotection after brain ischemia has been demonstrated by both preclinical and clinical studies. Studies to identify the effects of mild hypothermia on CYP450 metabolism in humans are limited and the translational significance of the observations in the rat model remains to be identified. The goal of this study is to evaluate the effects of therapeutic hypothermia and relevant disease model cardiac arrest (CA) on hepatic drug metabolism. Specifically, this study evaluated the effects of therapeutic hypothermia on specific CYP450-mediated drug metabolism in preclinical and in translational clinical studies. There are several conclusions can be made based on our study results. Mild hypothermia and cardiac arrest alter CYP activity in an isoform specific manner. Magnitude of the reduction is likely temperature, and extraction ratio specific. In animal model, the combination of hypothermia (33C) and CA was most likely to be associated with isoform specific decrease of enzyme activities with greater changes observed for CYP3A and CYP2E1. Hypothermia decreased the volume of distribution of multiple probe substrates. In healthy volunteers, we found significant correlation between temperature and the clearance of CYP3A probe drug midazolam. Short duration hypothermia studies with hepatically eliminated drugs suggest ~11% reduction in clearance per C change. Microdosed cocktail probes are likely to be very useful in PK study design in…
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