PT  - JOURNAL ARTICLE
AU  - David Hostler
AU  - Jiangquan Zhou
AU  - Michael A. Tortorici
AU  - Robert R. Bies
AU  - Jon C. Rittenberger
AU  - Philip E. Empey
AU  - Patrick M. Kochanek
AU  - Clifton W. Callaway
AU  - Samuel M. Poloyac
TI  - Mild Hypothermia Alters Midazolam Pharmacokinetics in Normal Healthy Volunteers
AID  - 10.1124/dmd.109.031377
DP  - 2010 May 01
TA  - Drug Metabolism and Disposition
PG  - 781--788
VI  - 38
IP  - 5
4099  - http://dmd.aspetjournals.org/content/38/5/781.short
4100  - http://dmd.aspetjournals.org/content/38/5/781.full
SO  - Drug Metab Dispos2010 May 01; 38
AB  - The clinical use of therapeutic hypothermia has been rapidly expanding due to evidence of neuroprotection. However, the effect of hypothermia on specific pathways of drug elimination in humans is relatively unknown. To gain insight into the potential effects of hypothermia on drug metabolism and disposition, we evaluated the pharmacokinetics of midazolam as a probe for CYP3A4/5 activity during mild hypothermia in human volunteers. A second objective of this work was to determine whether benzodiazepines and magnesium administered intravenously would facilitate the induction of hypothermia. Subjects were enrolled in a randomized crossover study, which included two mild hypothermia groups (4°C saline infusions and 4°C saline + magnesium) and two normothermia groups (37°C saline infusions and 37°C saline + magnesium). The lowest temperatures achieved in the 4°C saline + magnesium and 4°C saline infusions were 35.4 ± 0.4 and 35.8 ± 0.3°C, respectively. A significant decrease in the formation clearance of the major metabolite 1′-hydroxymidazolam was observed during the 4°C saline + magnesium compared with that in the 37°C saline group (p < 0.05). Population pharmacokinetic modeling identified a significant relationship between temperature and clearance and intercompartmental clearance for midazolam. This model predicted that midazolam clearance decreases 11.1% for each degree Celsius reduction in core temperature from 36.5°C. Midazolam with magnesium facilitated the induction of hypothermia, but shivering was minimally suppressed. These data provided proof of concept that even mild and short-duration changes in body temperature significantly affect midazolam metabolism. Future studies in patients who receive lower levels and a longer duration of hypothermia are warranted. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics