构建LPS诱导的急性炎症小鼠模型用于IDO1抑制剂药效动力学评价

 目的 构建急性炎症小鼠模型用于吲哚胺2， 3-双加氧酶1（indoleamine 2，3-dioxygenase 1，IDO1）抑制剂的药效动力学评价。方法 采用尾静脉注射或腹腔注射给予小鼠脂多糖（lipopolysaccharide，LPS），构建IDO1活性上调的急性炎症小鼠模型。模型小鼠灌胃给予IDO1抑制剂L-1-甲基色氨酸（L-1-methyl-tryptophan，L-1-MT）或TQ016，给药后不同时间点取血，HPLC检测小鼠血清中色氨酸（tryptophan，Trp）和犬尿氨酸（kynurenine，Kyn）含量，计算Kyn/Trp比值。采用IDO1活性上调引起的Trp浓度降低、Kyn浓度升高及Kyn/Trp比值增大，来评价IDO1抑制剂L-1-MT和TQ016对急性炎症小鼠血清中上调的IDO1活性的抑制效果。结果 尾静脉注射0.66 mg/kg LPS或腹腔注射5 mg/kg LPS均显著上调小鼠血清中IDO1活性。100 mg/kg L-1-MT在灌胃给药4 h后显著抑制模型小鼠血清中上调的IDO1活性。100 mg/kg TQ016在灌胃给药1、6、12、24和30 h后均显著抑制模型小鼠血清中上调的IDO1活性。TQ016呈剂量依赖性抑制模型小鼠血清中上调的IDO1活性。结论 LPS诱导的急性炎症小鼠模型适用于IDO1抑制剂的药效动力学评价。IDO1抑制剂TQ016具有良好的IDO1活性抑制效果。

Establishment of LPS-induced acute inflammation mouse model for the pharmacodynamics evaluation of IDO1 inhibitor

Objective To establish an acute inflammation mouse model for the pharmacodynamics evaluation of IDO1 inhibitor.Methods Lipopolysaccharide (LPS) was administrated to mice through tail vein intravenous injection or intraperitoneal injection to establish an acute inflammation mouse model with up-regulated IDO1 activity.The model mice were gavaged with IDO1 inhibitor L-1-methyl-tryptophan (L-1-MT) or TQ016.The blood samples were collected at different time points after administration.The contents of tryptophan (Trp) and kynurenine (Kyn) in serum of mice were detected by HPLC and the ratio of Kyn/Trp was calculated.The effects of IDO1 inhibitors (L-1-MT and TQ016) on the up-regulated IDO1 activity resulting in the decrease of Trp concentration, increase of Kyn concentration and Kyn/Trp ratio were evaluated.Results Tail vein intravenous injection of 0.66 mg/kg LPS or intraperitoneal injection of 5 mg/kg LPS both could significantly up-regulate IDO1 activity in the serum of mice. L-1-MT (100 mg/kg) significantly inhibited up-regulated IDO1 activity in serum 4 h after intragastric administration. TQ016 (100 mg/kg) significantly inhibited the up-regulated IDO1 activity in serum 1,6,12,24 or 30 h after intragastric administration. TQ016 inhibited the up-regulated IDO1 activity in serum in a dose-dependent manner.Conclusion LPS induced acute inflammation mouse model is suitable for the pharmacodynamics evaluation of IDO1 inhibitors. IDO1 inhibitor TQ016 has a good inhibitory effect on IDO1 activity.