title: Evaluation of hypothermia on the in vitro metabolism and binding and in vivo disposition of midazolam in rats.
abstract: The effect of hypothermia on the in vivo pharmacokinetics of midazolam was evaluated, with a focus on altered metabolism in the liver and binding to serum proteins. Rat primary hepatocytes were incubated with midazolam (which is metabolized mainly by CYP3A2) at 37, 32 or 28 °C. The Michaelis-Menten constant (Km) and maximum velocity (Vmax) of midazolam were estimated using the Michaelis-Menten equation. The Km of CYP3A2 midazolam remained unchanged, but the Vmax decreased at 28 °C. In rats, whose temperature was maintained at 37, 32 or 28 °C by a heat lamp or ice pack, the plasma concentrations of midazolam were higher, whereas those in the brain and liver were unchanged at 28 °C. The tissue/plasma concentration ratios were, however, increased significantly. The unbound fraction of midazolam in serum at 28 °C was half that at 37 °C. These pharmacokinetic changes associated with hypothermic conditions were due to reductions in CYP3A2 activity and protein binding.
authors.affiliation: Graduate School of Biomedical Sciences, Nagasaki University, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Miyamoto
authors.affiliation: Graduate School of Biomedical Sciences, Nagasaki University, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsueda
authors.affiliation: Department of Hospital Pharmacy, Nagasaki University Hospital, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Moritsuka
authors.affiliation: Graduate School of Biomedical Sciences, Nagasaki University, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Shimokawa
authors.affiliation: Graduate School of Biomedical Sciences, Nagasaki University, Japan.
authors.forename: Haruna
authors.initials: H
authors.lastname: Hirata
authors.affiliation: Graduate School of Biomedical Sciences, Nagasaki University, Japan.
authors.forename: Mikiro
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Department of Hospital Pharmacy, Nagasaki University Hospital, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sasaki
authors.affiliation: Graduate School of Biomedical Sciences, Nagasaki University, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Fumoto
authors.affiliation: Graduate School of Biomedical Sciences, Nagasaki University, Japan.
authors.forename: Koyo
authors.initials: K
authors.lastname: Nishida
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007035:Hypothermia / Q000097:blood*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008874:Midazolam / Q000097:blood* / Q000494:pharmacology; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
chemical_list: C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam
keywords: CYP3A2; distribution; midazolam; protein binding; therapeutic hypothermia