Optimization of midazolam dosage and pharmacokinetics of CYP3A probe substrate in rats
10.16438/j.0513-4870.2015-0811
- VernacularTitle:CYP3A探针底物咪达唑仑在大鼠体内的非线性药动学过程及剂量优化
- Author:
Xiao-ling QIN
1
;
Wen-hai DUAN
1
;
Xin-ping XUE
2
;
Xiao CHEN
3
;
Min HUANG
2
;
Hui-chang BI
2
Author Information
1. Guangdong Food and Drug Vocational College, Guangzhou 510520, China
2. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
3. The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
- Publication Type:COMMUNICATION
- Keywords:
midazolam;
CYP3A;
pharmacokinetics;
dosage optimization;
probe substrate
- From:
Acta Pharmaceutica Sinica
2016;51(5):834-
- CountryChina
- Language:Chinese
-
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.
