Mild hypothermia alters midazolam pharmacokinetics in normal healthy volunteers

David Hostler, Jiangquan Zhou, Michael A. Tortorici, Robert Bies, Jon C. Rittenberger, Philip E. Empey, Patrick M. Kochanek, Clifton W. Callaway, Samuel M. Poloyac

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)781-788
Number of pages8
JournalDrug Metabolism and Disposition
Volume38
Issue number5
DOIs
StatePublished - May 2010
Externally publishedYes

Fingerprint

Midazolam
Hypothermia
Healthy Volunteers
Magnesium
Pharmacokinetics
Temperature
Body Temperature Changes
Shivering
Induced Hypothermia
Cytochrome P-450 CYP3A
Benzodiazepines
Cross-Over Studies
Volunteers
Pharmaceutical Preparations
Population

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Hostler, D., Zhou, J., Tortorici, M. A., Bies, R., Rittenberger, J. C., Empey, P. E., ... Poloyac, S. M. (2010). Mild hypothermia alters midazolam pharmacokinetics in normal healthy volunteers. Drug Metabolism and Disposition, 38(5), 781-788. https://doi.org/10.1124/dmd.109.031377

Mild hypothermia alters midazolam pharmacokinetics in normal healthy volunteers. / Hostler, David; Zhou, Jiangquan; Tortorici, Michael A.; Bies, Robert; Rittenberger, Jon C.; Empey, Philip E.; Kochanek, Patrick M.; Callaway, Clifton W.; Poloyac, Samuel M.

In: Drug Metabolism and Disposition, Vol. 38, No. 5, 05.2010, p. 781-788.

Research output: Contribution to journalArticle

Hostler, D, Zhou, J, Tortorici, MA, Bies, R, Rittenberger, JC, Empey, PE, Kochanek, PM, Callaway, CW & Poloyac, SM 2010, 'Mild hypothermia alters midazolam pharmacokinetics in normal healthy volunteers', Drug Metabolism and Disposition, vol. 38, no. 5, pp. 781-788. https://doi.org/10.1124/dmd.109.031377
Hostler, David ; Zhou, Jiangquan ; Tortorici, Michael A. ; Bies, Robert ; Rittenberger, Jon C. ; Empey, Philip E. ; Kochanek, Patrick M. ; Callaway, Clifton W. ; Poloyac, Samuel M. / Mild hypothermia alters midazolam pharmacokinetics in normal healthy volunteers. In: Drug Metabolism and Disposition. 2010 ; Vol. 38, No. 5. pp. 781-788.
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