Therapeutic hypothermia decreases neurological damage in patients experiencing out-of-hospital cardiac arrest (CA). In addition to hypothermia, critically ill patients are treated with an extensive pharmacotherapeutic regimen. The majority of these medications are hepatically eliminated via the cytochrome P450 (CYP450) system. Changes in drug clearance could limit the putative benefit of hypothermic therapy. With the increased use of therapeutic hypothermia and the fact that critically ill patients receive multiple medications, it is crucial to understand the effects of hypothermia on the disposition and metabolism of drugs used in this population. Thus, it was the overall aim of this research to investigate the effects of therapeutic hypothermia on CYP450-mediated metabolism in an animal model of CA, in human liver microsomes, and in normal healthy subjects. Specifically, hypothermia produced a ~2 fold decrease in the systemic clearance (CLS) of intravenous chlorzoxazone, a specific CYP2E1 probe substrate, in a CA rat model when compared to CA rats treated under normothermic temperatures. The mechanism behind this decrease in CLS was a hypothermia-mediated decrease in the affinity of CYP2E1 for chlorzoxazone. We extended the experimental period to investigate the effects of hypothermia after re-warming, on CYP2E1 and CYP3A2 activity and expression. Our results indicate that rats with CA treated under normothermic temperatures demonstrated a significant decrease in the activities of CYP2E1 and CYP3A2, 24 hrs after injury compared to control. Furthermore, CA significantly decreased the expression of CYP3A2, but not the expression of CYP2E1. CA also produced a ~ 10-fold increase in plasma concentrations of interleukin-6 (IL-6) compared to Control. The CA-mediated reduction in CYP3A2 and CYP2E1 activity, mRNA, and the increase in IL-6 plasma concentrations was attenuated by hypothermia. We also investigated the effects of mild and moderate hypothermia on CYP2E1 and CYP3A4 enzyme kinetics in human liver microsomes. Both mild and moderate hypothermia significantly decreased the Vmax of CYP2E1 and CYP3A4. However, hypothermia increased the Km of CYP2E1 but not CYP3A4. These data demonstrate that mild and moderate hypothermia may produce isoform specific alterations of human CYP450-mediated metabolism. Lastly, in a pilot analysis, we showed that mild hypothermia may potentially alter the ClS and the volume of distribution (Vss) of midazolam in mildly hypothermic normal healthy volunteers.
Collectively, this work provides evidence that therapeutic hypothermia alters CYP450-mediated metabolism both during cooling and after re-warming. Based on the magnitude of these changes it is clear that intensivists should be cognizant of these alterations and monitor drug levels and outcomes in their patients when possible. In addition to increased clinical attention, future research efforts are essential to delineate precise dosing guidelines and mechanisms of the effects of hypothermia on drug disposition, metabolism, and response.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-04162007-161049 |
| Date | 17 April 2007 |
| Creators | Tortorici, Michael Andrew |
| Contributors | Patrick M Kochanek, MD, Samuel M Poloyac, PharmD, PhD, Michael Zemaitis, PhD, Raman Venkataramanan, PhD, Regis Vollmer, PhD, Robert Gibbs, PhD |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-04162007-161049/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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