厄洛替尼在Lewis肺癌小鼠时辰药代动力学特点及相关代谢酶昼夜节律性的研究

发布时间：2018-05-22 16:45

本文选题：厄洛替尼 + 时辰节律性　；参考：《青岛大学》2014年硕士论文

【摘要】：目的：本文探究了小分子靶向药物厄洛替尼在荷瘤小鼠的时间药代动力学特点以及小鼠体内相关肝药酶表达的昼夜节律。方法: 1.将雌性C57BL小鼠于严格控制人工昼夜(明期7：00～19：00；暗期190：0～7：00)条件下适应性饲养3周,后肢皮下接种Lewis肺癌细胞。 2.选种瘤成功后的小鼠分为六个给药组分别于8：00、12：00、16：00、20：00、24：00、4：00灌胃给予厄洛替尼150mg·kg-1,各组分别于给药后5、10、20、30、45nnin、1.5、3、5、8、12、16、24h摘眼球取血0.5mL,后立即处死小鼠,取肝脏组织冻存。 3.采用HPLC法测定厄洛替尼的血药浓度,按照非房室模型用WinNonlin软件计算药代动力学参数。 4.从肝脏组织中提取总RNA并采用qRT-PCR测定其中Cyp3all、Cyp3a13及Cyp1a2的mRNA表达随时间的变化情况。结果： 1.凌晨和上午(4：00、8：00、12：00)用药组的AUC和MRT明显高于其他时间用药组,20：00用药组的最低。Cmax的峰值出现在12：00用药组,而谷值是在20：00用药组。夜间用药组(20：00、24：00、4：00)的达峰时间与其他组相比均较小。CL的最大值出现在20：00用药组。 2.厄洛替尼在小鼠体内代谢的相关酶Cyp3all、Cyp3a13及Cyp1a2的mRNA表达均呈节律性波动。下午(12：00～16：00)以及夜间表达量明显高于凌晨和上午(4：00～8：00)。结论：不同用药时间对厄洛替尼的体内药动过程有显著影响,其药代动力学过程存在明显的时辰节律性。而小鼠体内肝药酶表达的昼夜节律性可部分解释厄洛替尼给药时辰节律性的产生机制。
[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.
【学位授予单位】：青岛大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R969.1

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