莫达非尼在小鼠体内的药动学-药效学联合研究

Pharmacokinetics-pharmacodynamics of modafinil in mice

对莫达非尼(modafinil,MOD)在小鼠体内的药动学和药效学进行联合研究,以阐明其关联性,为临床合理用药提供依据。以莫达非尼120 mg.kg-1对小鼠灌胃给药,采集给药后不同时间点血浆样本,用HPLC检测血浆药物浓度,分析平均血药浓度经时变化并计算药动学参数。以小鼠自主活动计数为药效学指标,观测MOD 120 mg.kg-1灌胃给药后不同时间段内小鼠自主活动量(计数)的变化,分析与血浆药物浓度变化的相关性。结果显示,MOD在小鼠体内药动学过程符合二室模型,t1/2α,t1/2β,tmax,Cmax,AUC0-∞分别为0.42 h,3.10 h,1.00 h,41.34 mg.L-1和142.22 mg.L-1.h。MOD使小鼠自主活动明显增多,持续约4 h,且与血浆药物浓度呈同步变化,二者间存在明显的相关性。

To guide the reasonable clinical application of modafinil （MOD）, pharmacokinetics and pharmacodynamics of MOD in mice and the correlation between them were investigated. Male mice （Kunming strain） were given a single oral dose of MOD （120 mg.kg- 1）. The plasma concentration of MOD was measured by HPLC and the pharmacokinetic parameters were calculated with DAS 3.0 software. For another batch of male Kunming strain mice, their locomotor activities were recorded by an infrared ray passive sensor after a same oral dose of MOD, and the synchronization and correlation between the changes of MOD plasma concentration and the locomotor activity induced by MOD were compared and analyzed. The results showed that the plasma concentration-time curve of MOD was fitted to two-compartment open model with a first order absorption. The main pharmacokinetic parameters t1/2α, t1/2β, tmax, Cmax and AUC0-∞ were 0.42 h, 3.10 h, 1.00 h, 41.34 mg.L-1 and 142.22 mg-L-1-h, respectively. MOD significantly increased locomotor activity and the effect lasted for about 4 h. The changes of MOD plasma concentration and the locomotor activity induced by MOD were synchronous. In conclusion, there is a significant correlation between the effect of MOD and its plasma concentration after administration of 120 mg-kg 1 in mice.