Pharmacokinetic-pharmacodynamic modeling of tolmetin antinociceptive effect in the rat using an indirect response model:: A population approach
Pharmacokinetic-pharmacodynamic modeling of tolmetin antinociceptive effect in the rat using an indirect response model:: A population approach
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DOI：
10.1023/a:1023273100270
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发表时间：
1998-10-01
期刊：
影响因子：
--
通讯作者：
Castañeda-Hernández, G
中科院分区：
文献类型：
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作者：
Flores-Murrieta, FJ;Ko, HC;Castañeda-Hernández, G
托美汀的药代动力学与抗伤感受效应之间的关系采用间接模型，采用群体方法进行表征。动物在右后肢关节内注射尿酸以诱导其功能障碍。功能障碍完全消除后，大鼠分别口服1、3.2、10、31.6、56.2或100 mg/kg的托美汀剂量，同时评估其抗伤感受效果和血托美汀浓度。托莫林产生了剂量依赖性的功能恢复，这与血药浓度没有直接关系。基于这些反应模式和托尔美汀通过抑制前列腺素合成来减少伤害感受的事实，使用了抑制性间接反应模型。采用非线性混合效应模型（NONMEM）将药代动力学（PK）和药效学（PD）数据同时拟合到单室模型和间接反应模型中。使用贝叶斯分析来描述响应的个体时间过程，并将总体参数作为先验估计。预测数据与观测数据吻合良好。群体分析显示，伤害性反应的最大抑制率为76%；IC50为9.22 μ g/ml。该IC50值与体外托咪汀诱导的aglandin后合成抑制（3.0 μ g/ml）相似。目前的结果表明，基于机制的PK-PD分析使用群体方法对定量个体反应是有用的，并且我们反映了给定药物在体内的实际作用机制。
The relationship between the pharmacokinetics and the antinociceptive effect of tolmetin was characterized by an indirect model using a population approach. Animals received an intra-articular injection of uric acid in the right hindlimb to induce its dysfunction. Once dysfunction was complete, rats received an oral tolmetin dose of 1, 3.2, 10, 31.6, 56.2, or 100 mg/kg and antinociceptive effect and blood tolmetin concentration were simultaneously evaluated. tolmerin produced a dose-dependent recovery of functionality, which was not directly related to blood concentration. An inhibitory indirect response model was used based on these response patterns and the fact that tolmetin reduced nociception by inhibiting prostaglandin synthesis. Pharmacokinetic (PK) and pharmacodynamic (PD) data were simultaneously fitted using nonlinear mixed effects modeling (NONMEM) to the one-compartment model and indirect response model. The individual time courses of the response were described using Bayesian analysis with population parameters as a priori estimates. There was good agreement between the predicted and observed data. Population analysis yielded a maximal inhibition of the nociceptive response of 76%; and an IC50 of 9.22 mu g/ml. This IC50 is similar to that for tolmetin-induced postaglandin synthesis inhibition in vitro (3.0 mu g/ml). The present results demonstrate that mechanism-based PK-PD analysis using a population approach is useful for quantitating individual responses as,well us reflecting the actual mechanism of action of a given drug in vivo.