抗肿瘤新药CPD7药效药动学特性研究

发布时间：2018-07-31 06:42

【摘要】：目的：作为一线抗肿瘤药-阿法替尼（Afatinib）的结构类似物，CPD7的药效活性及成药性成为新药开发的关键。本文主要对CPD7的药理活性以及药物代谢动力学特性展开研究，为其进一步开发奠定基础。方法：采用体外肿瘤细胞抑制实验测定CPD7在不同肿瘤细胞中的半数抑制浓度（IC50）；采用静脉以及灌胃给药后，测定CPD7的组织吸收、分布及排泄等药代动力学特征参数。采用微粒体孵育法，测定了CPD7在不同种属动物肝微粒体中的内在清除率，，并鉴定其主要代谢产物以及代谢酶。结果： CPD7在体外对八种肿瘤细胞具有不同程度的抑瘤活性,其中对人肺癌细胞（A549）和人肺癌细胞（NCI-H441）IC50分别是2.18μM和2.79μM。 CPD7在SD大鼠体内的药代动力学特性为：1）静脉注射后，平均血浆清除率（CL）和半衰期（t1/2）分别为40.8mL·min·kg-1和5.12h；不同剂量灌胃后测得的平均生物利用度（F）分别为33.2%（1.0mg·kg-1）、41.2%（3.0mg·kg-1）及51.1%（10mg·kg-1）；2）灌胃给药后，CPD7可较快向各组织分布，其中肺、小肠、胃、脾脏和肝脏中分布程度较高；CPD7在粪便中48h的累积排泄百分率为25.4±3.35%，在尿液中48h内的累积排泄百分率为0.191±0.120%，在胆汁中48h内的累积排泄百分率为2.22±0.890%。微粒体孵育结果表明：1）CPD7在小鼠、大鼠、比格犬、食蟹猴和人肝微粒体中的内在清除率分别为18.4、22.4、98.2、38.8和11.3μL min-1·mg-1，说明其体外代谢速率具有一定的种属差异性；2）在各种属肝微粒体中，CPD7的代谢主要是由N-去甲基及N-氧化反应介导。在人肝微粒体中参与代谢的主要酶为细胞色素氧化酶P450（CYP3A）及黄素单加氧化酶（FMO）。结论：本论文初步考察了CPD7的药理活性，并对其在体外及大鼠体内的药代动力学进行了全面的研究，为其新药开发提供了科学依据和丰富的数据支持。
[Abstract]:Aim: as a first-line antitumor drug, the structure analogue of afatinib (Afatinib) (Afatinib) has become the key to the development of new drugs. In this paper, the pharmacological activity and pharmacokinetic characteristics of CPD7 were studied, which laid a foundation for its further development. Methods: the inhibition concentration (IC50) of CPD7 in different tumor cells was measured by tumor cell inhibition assay in vitro, and the pharmacokinetic parameters of CPD7 were measured by intravenous and intragastric administration, such as tissue absorption, distribution and excretion of CPD7. The intrinsic clearance rate of CPD7 in liver microsomes of different species of animals was determined by microsomal incubation, and its main metabolites and metabolic enzymes were identified. Results: CPD7 had different inhibitory activity on eight kinds of tumor cells in vitro. The pharmacokinetic characteristics of CPD7 on human lung cancer cell line (A549) and human lung cancer cell line (NCI-H441) were 2.18 渭 M and 2.79 渭 M. CPD7 were injected intravenously into SD rats. The mean plasma clearance rate (CL) and half-life (t ~ (1 / 2) were 40.8mL min kg-1 and 5.12 h, respectively, and the average bioavailability (F) was 33.2% (1.0mg kg-1) 41.2% (3.0mg kg-1) and 51.1% (10mg kg-1) after different doses. The cumulative excretion percentage of CPD7 in feces was 25.4 卤3.35 in feces, 0.191 卤0.120 in urine within 48 hours, and 2.22 卤0.890 in bile. The results of microsomal incubation showed that the intrinsic clearance rates of CPD7 in mice, rats, Beagle dogs, crab monkeys and human liver microsomes were 18.422. 4 渭 L min-1 mg-1 and 18. 4 渭 L min-1 mg-1, respectively. 2) in various liver microsomes, the metabolism of CIP D7 was mainly mediated by N- demethylation and N- oxidation. The main enzymes involved in metabolism in human liver microsomes are cytochrome oxidase P450 (CYP3A) and flavin monoadduct oxidase (FMO). Conclusion: the pharmacological activity of CPD7 was investigated and its pharmacokinetics in vitro and in vivo was studied in order to provide scientific basis and abundant data support for the development of new drugs.
【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

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