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Evaluation of the effects of therapeutic hypothermia and cardiac arrest on specific cytochrome P450 isoform activity

Zhou, Jiangquan (2011) Evaluation of the effects of therapeutic hypothermia and cardiac arrest on specific cytochrome P450 isoform activity. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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 critically ill patients due to the potential linearity of PK of probe drugs and no drug-drug interaction in the cocktail combination. In addition, effect of cooling on receptor dynamic response is unknown on the current data. In conclusion, our results have shown the effect of CA and hypothermia with interaction on isoform specific activity. Given the prominent role of mild hypothermia in the management of patients with CA, further translational studies using clinically relevant drugs and pharmacokinetics-pharmacodynamics modeling are vital for validation and prediction of drug dosing in different disease and temperature states.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Date: 3 September 2011
Date Type: Completion
Defense Date: 28 June 2011
Approval Date: 3 September 2011
Submission Date: 15 August 2011
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: pharmacokinetics; drug metabolism; critical care medicine; in vivo probes; cardiac arrest; UPLC/MS/MS; cytochrome P450; Therapeutic hypothermia; population pharmacokinetic modeling
Other ID: etd-08152011-203732
Date Deposited: 09 Oct 2012 20:20
Last Modified: 15 Nov 2016 13:55


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