[Optimization of midazolam dosage and pharmacokinetics of CYP3A probe substrate in rats]

The study was conducted to evaluate the pharmacokinetics of midazolam (MDZ) under different oral dosages in rats, and determine the optimum oral dosage of MDZ, a CYP3 A probe substrate in vivo. Male Sprague-Dawley rats were given a single oral dosages of MDZ at 1,2,5,10,15 or 20 mg·kg(-1). Plasma concentrations of MDZ and its major metabolite 1-hydroxyl midazolam (1-OH MDZ) were determined at different time points using a validated LC-MS/MS method. Pharmacokinetic parameters were calculated using non-compartmental model. The C(max), AUC(0-t) and AUC0(∞) of MDZ and 1-OH MDZ were linearly increased over the dose range of 1-5 mg·kg(-1) (r > 0.99), but not at the dose of 15 or 20 mg·kg(-1). The AUC/Dose at 1-10 mg·kg(-1) were not significant different, but that of 15 or 20 mg·kg(-1) were significantly higher. No significant sedative reaction was observed in all the rats at dosages of 1-5 mg·kg(-1), however loss of righting reflex was observed in rats receiving dosages of 10-20 mg·kg(-1). In conclusion, the optimized oral dose of MDZ was 1-5 mg·kg(-1) when MDZ is used as the CYP3 A probe substrate in rats.