IDO抑制剂PCC0208009在结肠癌CT26荷瘤小鼠的PK/PD研究  

Pharmacokinetics/Pharmacodynamics Study of IDO Inhibitor PCC0208009 in Colon Carcinoma CT26-bearing Mice

作　　者：姜雪 李晓鹏 郑爽 王洪波[1] 田京伟[1] 杜广营[1] JIANG Xue;LI Xiao-peng;ZHENG Shuang;WANG Hong-bo;TIAN Jing-wei;DU Guang-ying(School of Pharmacy,Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shangdong,Key Laboratory of Molecular Pharmacology and Drug Evaluation(Yantai University),Ministry of Education,Yantai University,Yantai 264005,China)

机构地区：[1]烟台大学药学院分子药理和药物评价教育部重点实验室,烟台大学新型制剂与生物技术药物研究山东省高校协同创新中心,山东烟台264005

出　　处：《烟台大学学报（自然科学与工程版）》2020年第4期427-432,共6页Journal of Yantai University(Natural Science and Engineering Edition)

基　　金：山东省优秀中青年科学家科研奖励基金资助项目(BS2015YY012);烟台大学博士启动基金资助项目(YX13B29).

摘　　要：通过研究吲哚胺2,3-双加氧酶(IDO)抑制剂PCC0208009在结肠癌CT26荷瘤小鼠中的药代动力学(PK)和药效动力学(PD)特点,为后续IDO抑制剂的开发和临床治疗效果的预测提供参考依据.研究采用结肠癌CT26荷瘤小鼠,以Kyn/Trp为药效评价指标,考察IDO抑制剂PCC0208009在小鼠体内的药代动力学(PK)与药效动力学(PD)特点及相关性.单次灌胃给予200 mg/kg PCC0208009,药物在血浆中的T max、T 1/2、平均C max和AUC 0-last分别为0.25 h、6.22 h、13.3μg/mL和22.9 h·μg/mL,在肿瘤中分别为0.5 h、7.08 h、13.3μg/mL和17.5 h·μg/g;PCC0208009在给药后2~8 h内可有效抑制血浆和肿瘤中Kyn/Trp.单次或多次灌胃给予25~400 mg/kg PCC02080094 h时,PCC0208009在血浆和肿瘤中的药物浓度以及对Kyn/Trp的抑制作用均呈剂量依赖性.结果表明,PCC0208009在给药后2~8 h内能有效抑制荷瘤小鼠血浆和肿瘤的IDO活性,在血浆和肿瘤中的药物浓度及对IDO的抑制作用均呈剂量依赖性,PK和PD间具有较好的相关性.We study the pharmacokinetic(PK)and pharmacodynamic(PD)characteristics of indoleamine 2,3-dioxygenase(IDO)inhibitor PCC0208009 in colon cancer CT26 tumor-bearing mice to provide a reference for the development of IDO inhibitors and the prediction of clinical treatment effects.After a single gavage administration of 200 mg/kg PCC0208009,T max,T 1/2,average C max,and AUC 0-last of PCC0208009 in plasma are 0.25 h,6.22 h,13.3μg/mL and 22.9 hμg/g,respectively.The above parameters of PCC0208009 in tumors are 0.5 h,7.08 h,3.86μg/g,and 17.5 h·μg/g,respectively.PCC0208009 effectively inhibits Kyn/Trp in plasma and tumors within 2-8 h after drug administration.4 h after single or multiple gavage administration of 25-400 mg/kg PCC0208009,the concentrations of PCC0208009 and inhibitory effects on Kyn/Trp in plasma and tumors show dose-dependent changes.The results indicate that PCC0208009 effectively inhibits IDO activity in plasma and tumors within 2-8 h after administration,the drug concentrations and the inhibitory effects on IDO are dose-dependent,and there is a good correlation between PK and PD.

关 键 词：PCC0208009 吲哚胺2 3-双加氧酶 免疫治疗 Kyn/Trp 药效动力学 药代动力学 

分 类 号：R966[医药卫生—药理学]