Sato Yuhki, Motoishi Erina, Kakuba Rina, Nagatsuka Yuka, Abe Takuya, Fujii Yutaka
Department of Pharmaceutical Sciences, Fukuyama University, Fukuyama-Shi, Hiroshima, Japan.
Department of Clinical Engineering and Medical Technology, Niigata University of Health and Welfare, Niigata-Shi, Niigata, Japan.
Sci Rep. 2025 Jun 3;15(1):19363. doi: 10.1038/s41598-025-03949-x.
Extracorporeal membrane oxygenation (ECMO) is increasingly being used in intensive care units. However, it can alter drug pharmacokinetics and lead to underexposure associated with treatment failure. The aim of the present study was to determine the influence of ECMO on the pharmacokinetics of midazolam (MDZ). An in vivo rat model was developed using a bolus injection of MDZ, with concentration monitoring for 180 min. Rats that underwent ECMO were compared with a control group. Pharmacokinetic analysis of in vivo data (noncompartmental analysis and nonlinear mixed effects modeling) was performed to determine the influence of ECMO. The activity of the enzyme CYP3A, which catalyzes MDZ metabolism was examined in the livers of ECMO-treated rats. In vivo pharmacokinetic models were developed, showing an increase in the volume of distribution and the area under the curve, but a decreased the clearance, which was associated with decreased CYP3A activity. These results suggest that ECMO may affect the efficacy or increase the risk of side effects associated with MDZ.
体外膜肺氧合（ECMO）在重症监护病房中的应用越来越广泛。然而，它会改变药物的药代动力学，并导致因治疗失败而出现药物暴露不足的情况。本研究的目的是确定ECMO对咪达唑仑（MDZ）药代动力学的影响。使用MDZ单次静脉注射建立了大鼠体内模型，并进行180分钟的血药浓度监测。将接受ECMO治疗的大鼠与对照组进行比较。通过对体内数据进行药代动力学分析（非房室分析和非线性混合效应建模）来确定ECMO的影响。检测了接受ECMO治疗大鼠肝脏中催化MDZ代谢的CYP3A酶的活性。建立了体内药代动力学模型，结果显示分布容积和曲线下面积增加，但清除率降低，这与CYP3A活性降低有关。这些结果表明，ECMO可能会影响MDZ的疗效或增加其副作用风险。
