||Evaluation of hypothermia on the in vitro metabolism and binding and in vivo disposition of midazolam in rats
Miyamoto, Hirotaka ,
Matsueda, Satoshi ,
Moritsuka, Akihiro ,
Shimokawa, Kenta ,
Hirata, Haruna Nakashima, Mikiro ,
Sasaki, Hitoshi ,
Fumoto, Shintaro ,
Biopharmaceutics & Drug Disposition
489 , 2015-10 , John Wiley & Sons, Ltd.
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.