Evaluation of hypothermia on the in vitro metabolism and binding and in vivo disposition of midazolam in rats. (15th July 2015)

• Record Type: Journal Article
• Authors: Miyamoto, Hirotaka; Matsueda, Satoshi; Moritsuka, Akihiro; Shimokawa, Kenta; Hirata, Haruna; Nakashima, Mikiro; Sasaki, Hitoshi; Fumoto, Shintaro; Nishida, Koyo
• Is Part Of: Biopharmaceutics & drug disposition. Volume 36:Number 7(2015:Oct.)
• Page Start: 481
• Page End: 489
• Publication Date: 2015-07-15
• Subjects: Biopharmaceutics -- Periodicals; Drugs -- Metabolism -- Periodicals; Pharmacology -- Periodicals; Biopharmaceutics -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; 615.19
• DOI: 10.1002/bdd.1960
• Languages: English
• ISSNs: 0142-2782

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <p>The effect of hypothermia on the <italic>in vivo</italic> 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 (<italic>K</italic>_m) and maximum velocity (<italic>V</italic>_max) of midazolam were estimated using the Michaelis–Menten equation. The <italic>K</italic>_m of CYP3A2 midazolam remained unchanged, but the <italic>V</italic>_max 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. Copyright © 2015 John Wiley &amp; Sons, Ltd.</p> </abstract>