College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, Sichuan, China.
Chengdu Pharmoko Tech Corp., Ltd., Chengdu, 610041, China.
Sci Rep. 2019 Feb 5;9(1):1450. doi: 10.1038/s41598-018-38164-4.
Pro-inflammatory factors are important indicators for assessing inflammation severity and drug efficacy. Coptisine has been reported to inhibit LPS-induced TNF-α and NO production. In this study, we aim to build a pharmacokinetic-pharmacodynamic model to quantify the coptisine time course and potency of its anti-inflammatory effect in LPS-stimulated rats. The plasma and lung coptisine concentrations, plasma and lung TNF-α concentrations, plasma NO concentration, and lung iNOS expression were measured in LPS-stimulated rats after intravenous injection of three coptisine doses. The coptisine disposition kinetics were described by a two-compartment model. The coptisine distribution process from the plasma to the lung was described by first-order dynamics. The dynamics of plasma TNF-α generation and elimination followed zero-order kinetics and the Michaelis-Menten equation. A first-order kinetic model described the TNF-α diffusion process from the plasma to the lung. A precursor-pool indirect response model was used to describe the iNOS and NO generation induced by TNF-α. The inhibition rates of TNF-α production by coptisine (54.73%, 26.49%, and 13.25%) calculated from the simulation model were close to the decline rates of the plasma TNF-α AUC (57.27%, 40.33%, and 24.98%, respectively). Coptisine suppressed plasma TNF-α generation in a linear manner, resulting in a cascading reduction of iNOS and NO. The early term TNF-α response to stimulation is a key factor in the subsequent inflammatory cascade. In conclusion, this comprehensive PK-PD model provided a rational explanation for the interlocking relationship among TNF-α, iNOS and NO production triggered by LPS and a quantitative evaluation method for inhibition of TNF-α production by coptisine.
促炎因子是评估炎症严重程度和药物疗效的重要指标。黄连素有抑制 LPS 诱导的 TNF-α和 NO 产生的作用。在本研究中，我们旨在构建一个药代动力学-药效学模型，以量化 LPS 刺激大鼠中黄连的时间过程和抗炎作用强度。在 LPS 刺激大鼠中静脉注射三种黄连剂量后，测量血浆和肺组织中黄连浓度、血浆和肺组织中 TNF-α浓度、血浆中 NO 浓度和肺组织中 iNOS 表达。用两室模型描述黄连的处置动力学。黄连从血浆到肺的分布过程用一级动力学描述。血浆中 TNF-α的生成和消除动力学遵循零级动力学和米氏方程。一级动力学模型描述了 TNF-α从血浆到肺的扩散过程。采用前体池间接反应模型描述 TNF-α诱导的 iNOS 和 NO 的生成。模拟模型计算的黄连对 TNF-α生成的抑制率（54.73%、26.49%和 13.25%）与血浆 TNF-α AUC 的下降率（57.27%、40.33%和 24.98%）接近。黄连以线性方式抑制血浆 TNF-α生成，导致 iNOS 和 NO 的级联减少。LPS 刺激后早期 TNF-α反应是随后炎症级联的关键因素。总之，这个综合的 PK-PD 模型为 LPS 触发的 TNF-α、iNOS 和 NO 生成的连锁关系提供了合理的解释，并为黄连抑制 TNF-α生成提供了定量评估方法。
