本文選題：厄洛替尼 + 時(shí)辰節(jié)律性　； 參考：《青島大學(xué)》2014年碩士論文

【摘要】：目的： 本文探究了小分子靶向藥物厄洛替尼在荷瘤小鼠的時(shí)間藥代動(dòng)力學(xué)特點(diǎn)以及小鼠體內(nèi)相關(guān)肝藥酶表達(dá)的晝夜節(jié)律。方 法: 1.將雌性C57BL小鼠于嚴(yán)格控制人工晝夜(明期7：00～19：00；暗期190：0～7：00)條件下適應(yīng)性飼養(yǎng)3周,后肢皮下接種Lewis肺癌細(xì)胞。 2.選種瘤成功后的小鼠分為六個(gè)給藥組分別于8：00、12：00、16：00、20：00、24：00、4：00灌胃給予厄洛替尼150mg·kg-1,各組分別于給藥后5、10、20、30、45nnin、1.5、3、5、8、12、16、24h摘眼球取血0.5mL,后立即處死小鼠,取肝臟組織凍存。 3.采用HPLC法測(cè)定厄洛替尼的血藥濃度,按照非房室模型用WinNonlin軟件計(jì)算藥代動(dòng)力學(xué)參數(shù)。 4.從肝臟組織中提取總RNA并采用qRT-PCR測(cè)定其中Cyp3all、Cyp3a13及Cyp1a2的mRNA表達(dá)隨時(shí)間的變化情況。 結(jié)果： 1.凌晨和上午(4：00、8：00、12：00)用藥組的AUC和MRT明顯高于其他時(shí)間用藥組,20：00用藥組的最低。Cmax的峰值出現(xiàn)在12：00用藥組,而谷值是在20：00用藥組。夜間用藥組(20：00、24：00、4：00)的達(dá)峰時(shí)間與其他組相比均較小。CL的最大值出現(xiàn)在20：00用藥組。 2.厄洛替尼在小鼠體內(nèi)代謝的相關(guān)酶Cyp3all、Cyp3a13及Cyp1a2的mRNA表達(dá)均呈節(jié)律性波動(dòng)。下午(12：00～16：00)以及夜間表達(dá)量明顯高于凌晨和上午(4：00～8：00)。 結(jié)論： 不同用藥時(shí)間對(duì)厄洛替尼的體內(nèi)藥動(dòng)過(guò)程有顯著影響,其藥代動(dòng)力學(xué)過(guò)程存在明顯的時(shí)辰節(jié)律性。而小鼠體內(nèi)肝藥酶表達(dá)的晝夜節(jié)律性可部分解釋厄洛替尼給藥時(shí)辰節(jié)律性的產(chǎn)生機(jī)制。
[Abstract]:Objective: The characteristics of time-pharmacokinetics and circadian rhythm of liver drug enzyme expression in tumor-bearing mice were investigated. Square France: 1. The female C57BL mice were fed with Lewis lung cancer cells subcutaneously for 3 weeks under strict control (7: 00: 19: 00 in bright phase and 190: 0 7: 00 in dark phase), and the hind limbs were subcutaneously inoculated with Lewis lung cancer cells. 2. The mice with successful tumor were divided into six groups. The mice were given erlotinib 150mg kg-1 by gavage at 8: 00, 12: 00, 16: 00, 20: 00, 24: 00, 4: 00, respectively. The mice in each group were given 0.5 mL of blood from their eyeballs at 5: 10, 2030, 45nning, 1.5121624 hours, and then killed immediately, and the liver tissue was frozen. 3. The plasma concentration of erlotinib was determined by HPLC and the pharmacokinetic parameters were calculated by WinNonlin software according to the non-atrioventricular model. 4. Total RNA was extracted from liver tissue and the mRNA expression of Cyp3allus Cyp3a13 and Cyp1a2 was determined by qRT-PCR. Results: 1. The peak values of AUC and MRT in the drug group were significantly higher than those in the control group at 20: 00 in the morning and in the morning. The peak value of .Cmax in the 20: 00 group was at 12:00, while the valley value was at 20:00. The peak time of 20: 00 to 24: 00: 4: 00) of night-time group was smaller than that of other groups. The maximum value of CL appeared in 20:00 group. 2. The mRNA expression of erlotinib related enzymes Cyp3allus Cyp3a13 and Cyp1a2 fluctuated rhythmically in mice. In the afternoon, 12: 00 and 16: 00) and the number of nocturnal expressions was significantly higher than that of 4: 00 in the morning and 8: 00 in the morning. Conclusion: The pharmacokinetic process of erlotinib was significantly influenced by different drug use time, and its pharmacokinetic process was time-rhythmic. The circadian rhythm of liver drug enzyme expression in mice may partly explain the production mechanism of erlotinib at the time of administration.
【學(xué)位授予單位】：青島大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R969.1

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