新型选择性PDE10A抑制剂PR-1346的药代动力学研究

发布时间：2019-04-27 22:24

【摘要】：目的：抗精神分裂症新的药物靶标选择性PDE10A抑制剂不仅能改善精神分裂症的阳性症状，还具有改善精神分裂症阴性症状和认知功能障碍的作用，作为新型的精神分裂症治疗药物的开发其潜力巨大。本课题拟在研究新型选择性PDE10A抑制剂PR-1346的临床前药代动力学性质，探讨PR-1346的成药性。方法：1）PR-1346体外人，大鼠和小鼠肝微粒酶稳定性研究；2）PR-1346微粒体酶（CYP3A4，CYP1A2，CYP2C9，CYP2C19和CYP2D6）抑制作用研究；3）应用平衡透析法进行PR-1346血浆蛋白结合研究；4）PR-1346在Caco-2和MDCKII-hMDR1细胞转运系统中细胞穿透和P-gp外排研究；5）分别尾静脉和口服给予小鼠PR-1346进行小鼠体内药代动力学和脑组织分布研究。结果：1）PR-1346在人，大鼠和小鼠肝微粒体酶肝内在清除率分别为0.252mL/minute/kg，3.808mL/minute/kg，42.63mL/minute/kg；2）PR-1346（10μM）对2C9、2C19和2D6抑制分数分别为79.3%、90.4%和52.5%，表现出较强的抑制作用，对CYP3A4和1A2无抑制作用；3）PR-1346（1μM）在人，大鼠和小鼠血浆蛋白结合率均大于99%，且种属间无明显差异；4）Caco-2细胞转运系统中PR-1346穿透系数（PappA-B：1.46x10-6cm/s， PappB-A：4.66x10-6cm/s），外排比3.0，，MDCKII-hMDR1细胞转运系统中PR-1346穿透系数（PappA-B：0.96x10-6cm/s，PappB-A：1.49x10-6cm/s），外排比1.17；5）小鼠口服PR-1346（2mg/kg）的消除半衰期为8.8小时，最大血药浓度为974.3ng/mL，曲线下面积（AUC）1178.9ng/mL*hour；清除率（CL）为6.1ng/mL/kg；生物利用度（Bioavailability%）87.4%。PR-1346给药后药物脑组织浓度至2小时达到峰浓度，在8小时内PR-1346脑组织浓度始终维持在高水平（244.1~528.8ng/mL），于24小时后脑组织内PR-1346浓度降至很低水平。结论：PR-1346在人，大鼠和小鼠肝微粒体酶稳定性表现较好，且存在明显种属差异；PR-1346（10μM）对CYP3A4，1A2亚型无明显抑制作用，对CYP2C9，2C19，CD6抑制作用较强；细胞穿透和外排实验发现PR-1346为中等穿透低外排化合物；PR-1346（1μM）为高血浆蛋白结合；PR-1346小鼠体内暴露量高，其生物利用度达到87.4%，同时其脑内浓度可在较长时间内维持于高水平，与体内药效和体外代谢结果基本一致。综上，我们认为新型PDE10A抑制剂PR-1346具有良好的药代动力学性质，具备较好的开发价值和应用前景。
[Abstract]:Objective: selective PDE10A inhibitor, a new drug target for anti-schizophrenia, can not only improve the positive symptoms of schizophrenia, but also improve the negative symptoms and cognitive dysfunction of schizophrenia. As a new type of schizophrenia treatment drugs, the development of its potential is enormous. The purpose of this study is to study the preclinical pharmacokinetic properties of a new selective PDE10A inhibitor, PR-1346, and to explore the formation of PR-1346. Methods: 1) the stability of liver microzyme in PR-1346 human, rat and mouse, 2) the inhibitory effect of PR-1346 microsomase (CYP3A4,CYP1A2,CYP2C9,CYP2C19 and CYP2D6), 3) the study of PR-1346 protein binding by equilibrium dialysis, and 2) the study of the inhibition of PR-1346 microsomase (CYP3A4,CYP1A2,CYP2C9,CYP2C19 and CYP2D6), and 3) the study of protein binding of PR-1346 by equilibrium dialysis. 4) the study of cell penetration and P-gp efflux of PR-1346 in Caco-2 and MDCKII-hMDR1 cell transport system, and (5) the pharmacokinetics and brain tissue distribution of PR-1346 in mice were studied by oral administration of PR-1346 in tail vein and tail vein, respectively. Results: 1) the intrahepatic clearance rates of PR-1346 in human, rat and mouse liver microsomes were 0.252 mL / kg, 3.808 mL / kg, 42.63 mL / min / kg and 42.63 mL / kg / kg, respectively.Results: (1) the enzyme clearance rates in human, rat and mouse liver microsomes were 0.252 mL / kg, 3.808 mL / kg and 42.63 mL / kg, respectively. 2) the inhibitory fraction of PR-1346 (10 渭 M) on 2C9, 2C19 and 2D6 was 79.3%, 90.4% and 52.5%, respectively, which showed a strong inhibitory effect on CYP3A4 and 1A2. 3) the binding rate of PR-1346 (1 渭 M) in human, rat and mouse plasma protein was more than 99%, and there was no significant difference between species and genera. 4) PR-1346 penetration coefficient (PappA-B:1.46x10-6cm/s, PappB-A:4.66x10-6cm/s), efflux ratio 3.0, in Caco-2 cell transport system. The PR-1346 penetration coefficient (PappA-B:0.96x10-6cm/s,PappB-A:1.49x10-6cm/s) and efflux ratio in MDCKII-hMDR1 cell transport system were 1.17; 5) the elimination half-life of oral PR-1346 (2mg/kg) was 8.8h, the maximum plasma concentration was 974.3 ng / mL, the area under the curve was (AUC) 1178.9 ng / L / hour, the clearance rate of (CL) was 6.1 ng / mL / kg, the clearance rate was 6.1ng / ml / kg. After bioavailability (Bioavailability%) 87.4%.PR-1346 administration, the brain tissue concentration of PR-1346 reached the peak concentration at 2 hours, and remained at high level (244.1~528.8ng/mL) for 8 hours. After 24 hours, the concentration of PR-1346 in brain tissue decreased to a very low level. Conclusion: PR-1346 has good stability in human, rat and mouse liver microsomes, and there are obvious species differences, but PR-1346 (10 渭 M) has no obvious inhibitory effect on CYP3A4,1A2 subtype, but has a strong inhibitory effect on CYP2C9,2C19,CD6. The results of cell penetration and efflux assay showed that PR-1346 was a medium penetrating and low efflux compound, and PR-1346 (1 渭 M) was a high plasma protein binding agent. The bioavailability of PR-1346 mice was 87.4%, and the brain concentration could be maintained at a high level for a long time, which was basically consistent with the efficacy in vivo and metabolism in vitro. In conclusion, we think that PR-1346, a new inhibitor of PDE10A, has good pharmacokinetic properties, and has good development value and application prospect.
【学位授予单位】：苏州大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R965

【共引文献】