Pharmacokinetics and bioavailability of midazolam after intravenous, subcutaneous, intraperitoneal and oral administration under a chronic food-limited regimen: Relating DRL performance to pharmacokinetics
Pharmacokinetics and bioavailability of midazolam after intravenous, subcutaneous, intraperitoneal and oral administration under a chronic food-limited regimen: Relating DRL performance to pharmacokinetics
复制标题
DOI：
10.1007/bf02246454
复制
发表时间：
1996-08-01
影响因子：
3.4
通讯作者：
Smith, C
中科院分区：
文献类型：
--
作者：
Lau, CE;Ma, F;Smith, C
咪达唑仑对动物行为的影响通常在长期限食方案下进行评价，该方案用于实施食物强化性能，但缺乏相应的药代动力学。本研究在食物受限大鼠中研究了咪达唑仑IV、SC、IP和PO给药后的药代动力学。二室模型最好地描述了四种给药途径的浓度-时间曲线。咪达唑仑吸收迅速，三种血管外给药途径均在7 min内达到峰浓度。中央室的平均分布容积和清除率分别为0.77 l/kg和2.03 l/h/kg。四种给药途径的咪达唑仑消除半衰期范围为23.1 - 49.5 min，未检出代谢物。平均绝对生物利用度具有给药途径依赖性：39.3%（SC）、19.2%（IP）和4.6%（PO）。在食物有限的大鼠中发现的口服生物利用度明显较低，与自由进食大鼠报告的值（45%）形成对比。虽然IP途径有时产生最高的最大浓度，但血清咪达唑仑浓度-时间曲线可变，但确实对应于各自的镇静反应。SC、IP和PO给药后的DRL 45-s性能进一步支持使用SC给药途径（而非IP途径）研究咪达唑仑剂量-反应关系的可行性。根据DRL性能评估的生物利用度值也与测定的药代动力学值一致。
The effects of midazolam on animal behavior often are evaluated under a chronically food-limited regimen, which is used to implement food-reinforced performance, but the corresponding pharmacokinetics are lacking. The present study investigated the pharmacokinetics of midazolam after IV, SC, IP, and PO administration in food-limited rats. A two-compartment model best described the concentration-time profiles for the four routes of administration. The rate of midazolam absorption was rapid, and peak concentrations were attained in less than 7 min for the three extravascular routes. The mean volume of distribution of the central compartment and clearance were 0.77 l/kg and 2.03 l/h per kg, respectively. Midazolam elimination half-lives for the four routes of administration ranged from 23.1 to 49.5 min, and metabolites could not be detected. The mean absolute bioavailability was route-dependent: 39.3% (SC) 19.2% (IP) and 4.6% (PO). The markedly low oral bioavailability found in food-limited rats contrasted to the value reported for free-feeding rats (45%). Although the IP route yielded the highest maximum concentration on occasion, serum midazolam concentration-time profiles were variable, but did correspond to respective sedative responses. DRL 45-s performance after SC, IP, and PO administration further supported the advisability of using the SC route of administration, as opposed to the IP route, for studying midazolam dose-response relations. The bioavailability values assessed from DRL, performance also agree with the measured pharmacokinetic values.