Evaluation of hypothermia on the in vitro metabolism and binding and in vivo disposition of midazolam in rats
Evaluation of hypothermia on the in vitro metabolism and binding and in vivo disposition of midazolam in rats
复制标题
低温对大鼠咪达唑仑体外代谢、结合及体内分布的评价
DOI：
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发表时间：
2015
影响因子：
2.1
通讯作者：
K. Nishida
中科院分区：
文献类型：
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作者：
Hirotaka Miyamoto;S. Matsueda;Akihiro Moritsuka;K. Shimokawa;Haruna Hirata;M. Nakashima;H. Sasaki;S. Fumoto;K. Nishida
评价了低温对咪达唑仑体内药代动力学的影响，重点是肝脏代谢的改变和与血清蛋白的结合。将大鼠原代肝细胞与咪达唑仑（主要通过CYP 3A 2代谢）在37、32或28 °C下孵育。用米氏方程估计咪达唑仑的米氏常数（Km）和最大流速（Vmax）。CYP 3A 2咪达唑仑的Km保持不变，但Vmax在28 °C时降低。在通过热灯或冰袋将体温维持在37、32或28 °C的大鼠中，咪达唑仑的血浆浓度较高，而在28 °C下，大脑和肝脏中的咪达唑仑浓度不变。然而，组织/血浆浓度比显著增加。28 ℃时血清中咪达唑仑的未结合分数是37 ℃时的一半。这些与低温条件相关的药代动力学变化是由于CYP 3A 2活性和蛋白结合的降低。版权所有© 2015约翰威利父子有限公司.
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. Copyright © 2015 John Wiley & Sons, Ltd.
DOI：
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发表时间：
1989
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
--
作者：
J. Huijzer;J. Adams;J. Jaw;G. Yost
通讯作者：
J. Huijzer;J. Adams;J. Jaw;G. Yost
影响因子：
4.1
作者：
DEMONTELLANO, PRO;MATHEWS, JM
通讯作者：
MATHEWS, JM