Pharmacokinetics of midazolam and hepatic cytochrome P450 3A activity in an in vivo extracorporeal membrane oxygenation rat model

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.