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Evaluation of hypothermia on the in vitro metabolism and binding and in vivo disposition of midazolam in rats


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Title: Evaluation of hypothermia on the in vitro metabolism and binding and in vivo disposition of midazolam in rats
Authors: Miyamoto, Hirotaka / Matsueda, Satoshi / Moritsuka, Akihiro / Shimokawa, Kenta / Hirata, Haruna / Nakashima, Mikiro / Sasaki, Hitoshi / Fumoto, Shintaro / Nishida, Koyo
Issue Date: Oct-2015
Publisher: John Wiley & Sons, Ltd.
Citation: Biopharmaceutics & Drug Disposition, 36(7), pp.481-489; 2015
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℃. 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℃. In rats, whose temperature was maintained at 37, 32 or 28℃ 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℃. The tissue/plasma concentration ratios were, however, increased significantly. The unbound fraction of midazolam in serum at 28 °C was half that at 37℃. These pharmacokinetic changes associated with hypothermic conditions were due to reductions in CYP3A2 activity and protein binding.
Keywords: therapeutic hypothermia / midazolam / CYP3A2 / protein binding / distribution
URI: http://hdl.handle.net/10069/36010
ISSN: 01422782
DOI: 10.1002/bdd.1960
Rights: © 2015 John Wiley & Sons, Ltd. / This is the peer reviewed version of the following article: Biopharmaceutics & Drug Disposition, 36(7), pp.481-489; 2015, which has been published in final form at http://dx.doi.org/10.1002/bdd.1960 This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Type: Journal Article
Text Version: author
Appears in Collections:Articles in academic journal

Citable URI : http://hdl.handle.net/10069/36010

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