【摘要】：目的：作為一線抗腫瘤藥-阿法替尼（Afatinib）的結構類似物，CPD7的藥效活性及成藥性成為新藥開發(fā)的關鍵。本文主要對CPD7的藥理活性以及藥物代謝動力學特性展開研究，為其進一步開發(fā)奠定基礎。 方法：采用體外腫瘤細胞抑制實驗測定CPD7在不同腫瘤細胞中的半數(shù)抑制濃度（IC50）；采用靜脈以及灌胃給藥后，測定CPD7的組織吸收、分布及排泄等藥代動力學特征參數(shù)。采用微粒體孵育法，測定了CPD7在不同種屬動物肝微粒體中的內在清除率，，并鑒定其主要代謝產(chǎn)物以及代謝酶。 結果： CPD7在體外對八種腫瘤細胞具有不同程度的抑瘤活性,其中對人肺癌細胞（A549）和人肺癌細胞（NCI-H441）IC50分別是2.18μM和2.79μM。 CPD7在SD大鼠體內的藥代動力學特性為：1）靜脈注射后，平均血漿清除率（CL）和半衰期（t1/2）分別為40.8mL·min·kg-1和5.12h；不同劑量灌胃后測得的平均生物利用度（F）分別為33.2%（1.0mg·kg-1）、41.2%（3.0mg·kg-1）及51.1%（10mg·kg-1）；2）灌胃給藥后，CPD7可較快向各組織分布，其中肺、小腸、胃、脾臟和肝臟中分布程度較高；CPD7在糞便中48h的累積排泄百分率為25.4±3.35%，在尿液中48h內的累積排泄百分率為0.191±0.120%，在膽汁中48h內的累積排泄百分率為2.22±0.890%。微粒體孵育結果表明：1）CPD7在小鼠、大鼠、比格犬、食蟹猴和人肝微粒體中的內在清除率分別為18.4、22.4、98.2、38.8和11.3μL min-1·mg-1，說明其體外代謝速率具有一定的種屬差異性；2）在各種屬肝微粒體中，CPD7的代謝主要是由N-去甲基及N-氧化反應介導。在人肝微粒體中參與代謝的主要酶為細胞色素氧化酶P450（CYP3A）及黃素單加氧化酶（FMO）。 結論：本論文初步考察了CPD7的藥理活性，并對其在體外及大鼠體內的藥代動力學進行了全面的研究，為其新藥開發(fā)提供了科學依據(jù)和豐富的數(shù)據(jù)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 鹵3.35 in feces, 0.191 鹵0.120 in urine within 48 hours, and 2.22 鹵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.
【學位授予單位】：蘇州大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R965

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