Optimization of midazolam dosage and pharmacokinetics of CYP3A probe substrate in rats / 药学学报

ABSTRACT

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 CYP3A 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 Cmax, AUC0-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 CYP3A probe substrate in rats.