奥沙西泮对个体大鼠抗惊厥作用的药代动力学-药效学建模

Pharmacokinetic-pharmacodynamic modelling of the anticonvulsant effect of oxazepam in individual rats.

作者信息

Dingemanse J, Voskuyl R A, Langemeijer M W, Postel-Westra I, Breimer D D, Meinardi H, Danhof M

机构信息

Center for Bio-Pharmaceutical Sciences, University of Leiden, The Netherlands.

出版信息

Br J Pharmacol. 1990 Jan;99(1):53-8. doi: 10.1111/j.1476-5381.1990.tb14653.x.

DOI:10.1111/j.1476-5381.1990.tb14653.x

PMID:2331575

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1917521/

Abstract

The purpose of this investigation was to examine in vivo drug-concentration anticonvulsant effect relationships of oxazepam in individual rats following administration of a single dose. 2. Whole blood concentration vs time profiles of oxazepam were determined following administration of doses of 4, 8 and 12 mg kg-1. The pharmacokinetics could be described by an open 2-compartment pharmacokinetic model. Following 12 mg kg-1 the values (mean +/- s.e., n = 11) of clearance and volume of distribution were 28 +/- 2 ml min-1 kg-1 and 2.6 +/- 0.31 kg-1, respectively, and were not significantly different from the values obtained at the other doses. 3. The anticonvulsant effect was quantitated by a new technique which allows repetitive determination of the convulsive threshold by direct cortical stimulation within one rat. Significant dose-dependent elevations of the seizure threshold were observed. 4. By pharmacokinetic-pharmacodynamic modelling, a log-linear relationship was found between concentration and anticonvulsant effect. Following 12 mg kg-1 the values (mean +/- s.e., n = 11) of the pharmacodynamic parameters slope and minimal effective concentration (Cmin) were 243 +/- 27 microA and 0.11 +/- 0.02 mg l-1, respectively and not significantly different from the values obtained at the other doses. 5. In a repeatability study the pharmacodynamic parameters were determined twice on two different occasions with an interval of two weeks in the same group of 11 rats. The inter-animal variability in the pharmacodynamic parameter slope was 46%, whereas the intra-animal variability was 24 +/- 18%. The value of the minimal effective concentration was in each animal and on each occasion close to zero within the relatively narrow range of 0.01-0.30mgI. 6. The results of this study showed that it is possible to determine in vivo concentration-anticonvulsant effect relationships of oxazepam under non-steady-state conditions in individual rats. The anti-convulsant effect of oxazepam appeared to be a rapidly reversible direct effect and acute tolerance did not develop within the time frame of the experiments.

摘要

本研究的目的是在单剂量给药后，研究奥沙西泮在个体大鼠体内的药物浓度与抗惊厥作用的关系。2. 分别给予4、8和12mg/kg剂量的奥沙西泮后，测定了全血浓度随时间的变化曲线。其药代动力学可用开放二室药代动力学模型描述。给予12mg/kg剂量后，清除率和分布容积的值（平均值±标准误，n = 11）分别为28±2ml·min⁻¹·kg⁻¹和2.6±0.31kg⁻¹，与其他剂量所得值无显著差异。3. 采用一种新技术对惊厥阈值进行重复测定，该技术可通过直接皮层刺激在同一只大鼠体内定量抗惊厥作用。观察到惊厥阈值有显著的剂量依赖性升高。4. 通过药代动力学-药效学建模，发现浓度与抗惊厥作用之间呈对数线性关系。给予12mg/kg剂量后，药效学参数斜率和最小有效浓度（Cmin）的值（平均值±标准误，n = 11）分别为243±27μA和0.11±0.02mg/L，与其他剂量所得值无显著差异。5. 在一项重复性研究中，对同一组11只大鼠在两个不同时间间隔两周的情况下，两次测定药效学参数。药效学参数斜率的动物间变异性为46%，而动物内变异性为24±18%。在0.01 - 0.30mg/L相对较窄的范围内，每只动物每次的最小有效浓度值均接近零。6. 本研究结果表明，在个体大鼠的非稳态条件下，有可能确定奥沙西泮的体内浓度-抗惊厥作用关系。奥沙西泮的抗惊厥作用似乎是一种快速可逆的直接作用，并且在实验时间范围内未出现急性耐受性。