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

Autor: Miyamoto, Hirotaka, Matsueda, Satoshi, Moritsuka, Akihiro, Shimokawa, Kenta, Hirata, Haruna, Nakashima, Mikiro, Sasaki, Hitoshi, Fumoto, Shintaro, Nishida, Koyo
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Zdroj: Biopharmaceutics & Drug Disposition. 36(7):481-489
ISSN: 0142-2782
Popis: 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.
Biopharmaceutics & Drug Disposition, 36(7), pp.481-489; 2015
Databáze: OpenAIRE
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