State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism & Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
PLoS One. 2013;8(1):e54981. doi: 10.1371/journal.pone.0054981. Epub 2013 Jan 24.
A mechanism-based model was developed to describe the time course of lipopolysaccharide-induced depressive-like behavior and azithromycin pharmacodynamics in mice. The lipopolysaccharide-induced disease progression was monitored by lipopolysaccharide, proinflammatory cytokines, and kynrenine concentration in plasma. The depressive-like behavior was investigated by forced swimming test and tail suspension test. Azithromycin was selected to inhibit the surge of proinflammatory cytokines induced by lipopolysaccharide. Disease progression model and azithromycin pharmacodynamics were constructed from transduction and indirect response models. A delay in the onset of increased proinflammatory cytokines, kynrenine, and behavior test compared to lipopolysaccharide was successfully characterized by series transduction models. The inhibition of azithromycin on proinflammatory cytokines was described by an indirect response model. After lipopolysaccharide challenging, the proinflammatory cytokines, kynrenine and behavior tests would peak approximately at 3, 12, and 24 h respectively, and then the time courses slowly declined toward a baseline state after peak response. During azithromycin administration, the peak levels of proinflammatory cytokines, kynrenine and behavior indexes decreased. Model parameters indicated that azithromycin significantly inhibited the proinflammatory cytokines level in plasma and improved the depressive-like behavior induced by inflammation. The integrated model for disease progression and drug intervention captures turnovers of proinflammatory cytokines, kynrenine and the behavior results in the different time phases and conditions.
建立了一个基于机制的模型来描述脂多糖诱导的抑郁样行为和阿奇霉素在小鼠中的药效动力学。通过脂多糖、促炎细胞因子和血浆中犬尿氨酸浓度监测脂多糖诱导的疾病进展。通过强迫游泳试验和悬尾试验研究抑郁样行为。选择阿奇霉素抑制脂多糖诱导的促炎细胞因子激增。通过转导和间接反应模型构建疾病进展模型和阿奇霉素药效动力学。通过串联转导模型成功地描述了与脂多糖相比，促炎细胞因子、犬尿氨酸和行为测试的起始时间延迟。间接反应模型描述了阿奇霉素对促炎细胞因子的抑制作用。脂多糖挑战后，促炎细胞因子、犬尿氨酸和行为测试的峰值分别约在 3、12 和 24 h 左右，然后在达到峰值反应后，时间过程缓慢下降至基线状态。在阿奇霉素给药期间，促炎细胞因子、犬尿氨酸和行为指标的峰值水平降低。模型参数表明，阿奇霉素显著抑制了血浆中促炎细胞因子的水平，并改善了炎症引起的抑郁样行为。疾病进展和药物干预的综合模型捕获了不同时间阶段和条件下促炎细胞因子、犬尿氨酸和行为结果的周转。
