维格列汀衍生物YHX-13在小鼠体内的药代动力学及组织分布研究

发布时间：2018-02-01 11:07

本文关键词： YHX-13 维格列汀药代动力学组织分布　出处：《重庆医科大学》2014年硕士论文　论文类型：学位论文

【摘要】：如今糖尿病患病率呈逐年上升的趋势，已经成为继肿瘤和心血管疾病之后，人类生命健康的第三大杀手。目前中国是全球范围内糖尿病增长最快的地区，并将成为世界糖尿病第一大国，患病人群以II型糖尿病为主，所占比例达到了93.7％。DDP-IV抑制剂作为一类新的口服降糖药物，应用于II型糖尿病的治疗中，其对血糖控制良好的安全性、有效性以及耐受性已经在大量的临床试验与实际应用中得到了充分的证实。维格列汀是一种高选择性的DDP-IV底物抑制剂，通过与DDP-IV形成可逆的共价键而紧密结合，缓慢解离，解离时间达到了55min，因而可以更为强效的抑制DDP-IV活性。重庆医科大学药物化学实验室通过对维格列汀结构的修饰，并进行体外活体筛选，得到了一系列维格列汀衍生物，，YHX-13是其中活性较好的衍生物之一。本实验通过对YHX-13的药代动力学及组织分布研究，可以考察该衍生物的药理学相关性质，为新药的研发提供理论依据。第一章：维格列汀衍生物YHX-13检测方法的建立及药代动力学研究目的：建立了维格列汀衍生物YHX-13在小鼠血浆中的含量测定方法，研究了其在小鼠体内的药代动力学规律。方法：通过灌胃和尾静脉注射两种方式给药昆明小鼠，在相应时间点眼眶取血，采用MCX固相萃取法处理生物样品，高效液相色谱法，以乙腈和磷酸二氢钾（40:60）作为流动相，检测小鼠血浆中YHX-13的含量，求得相关药代动力学参数及生物利用度。结果：采用HPLC法测定维格列汀衍生物YHX-13在小鼠血浆中的含量，峰形良好，与内标能够完全分离，在100~4000ng/mL范围内有良好的线性关系，相关系数r=0.9993；日内精密度RSD在7.2%~12.2%之间，日间精密度RSD在8.6%~13.3%之间；回收率在96.7~106.65%之间，RSD在4.86~6.01%之间；室温放置24h的稳定性和反复冻融5次后的稳定性均良好。口服药代动力学参数：Cmax=1557.11ng/mL、Tmax=30min、AUC0~∞=358232ng·min/mL、AUC0~t=159898ng·min/mL、CL=41.8723mL/min/kg、t1/2=740.784min、MRT=932.258min、Vss=39035.7mL/kg；尾静脉注射药代动力学参数：Cmax=1610.22ng/mL、 Tmax=3min、 AUC0~∞=79203.6ng·min/mL、AUC0~t=66177.7ng·min/mL、CL=63.1284mL/min/kg、t1/2=101.103min、MRT=125.331min、Vss=7911.93mL/kg，生物利用度F为80.54%。结论：该HPLC法相关条件用于YHX-13在小鼠血浆中的含量检测灵敏度好、准确性高、有较好的重复性，使用于YHX-13在小鼠体内的药代动力学研究，能够得到良好的相关参数和生物利用度。第二章：维格列汀衍生物YHX-13在小鼠体内的组织分布研究目的：建立了HPLC法测定YHX-13在小鼠组织中的含量测定方法，考察了其在小鼠组织中的分布情况。方法：通过灌胃给药昆明小鼠，分别于吸收相时间点、分布相时间点和消除相时间点断头处死，取出相应时间点的组织心、肝、脾、肺、肾、脑，测量相应时间点各组织中YHX-13的含量。结果：YHX-13在小鼠各组织匀浆液中能与内标峰完全分离，且不受到生物样品中内源性杂质的干扰；在100~4000ng/mL范围内有良好的线性关系，相关系数r均大于0.99；的日内精密度RSD≤11.01%，日间精密度RSD≤12.13%；回收率为95.54%~104.31%，RSD为3.2%~8.66%，均能满足YHX-13在生物样品中的检测要求，且室温放置24h和反复冻融5次后的稳定性良好。结论：该HPLC法能够准确测出YHX-13在小鼠各组织中的含量，经过灌胃给药后，YHX-13主要分布于肺部，其次是肾，肝和脾中有较少分布。
[Abstract]:Now the prevalence of diabetes is increasing year by year, has become the following cardiovascular disease and cancer, human life and health of the third major killers. Currently Chinese is worldwide diabetes the fastest growing region, and will become the world's first big population with diabetes, type II diabetes, the proportion reached as 93.7%.DDP-IV inhibitors a new class of oral hypoglycemic drugs, treatment for type II diabetes, the safety of good glycemic control, effectiveness and tolerability has been fully confirmed in clinical trials and a large number of practical applications.
Vee Glenn Dean is a highly selective inhibitor of DDP-IV substrate, through covalent bond formation and reversible DDP-IV and closely, slow dissociation, dissociation time reached 55min, so it can be more potent to inhibit the activity of DDP-IV. Laboratory of Medical University Of Chongqing pharmaceutical chemistry by modification of vildagliptin structure, and in vitro and in vivo screening, a series of vildagliptin derivatives, YHX-13 is one of the better derivatives activity. Study on pharmacokinetics and tissue distribution of YHX-13 can be investigated through the experiment, pharmacology of the derivative related properties, and provide a theoretical basis for the development of new drugs. The first chapter: the establishment and pharmacokinetic study of Vee Glenn Dean derivatives YHX-13 detection method
Objective: to establish a method for determination of the Vee Glenn Dean derivative YHX-13 in mouse plasma and study its pharmacokinetics in mice. Methods: by intragastric administration and intravenous injection of two administered Kunming mice, blood samples were taken at the corresponding time point of orbital, treated by MCX biological samples by solid phase extraction, high performance liquid chromatography with acetonitrile and potassium dihydrogen phosphate (40:60) as mobile phase, detection of the content of YHX-13 in plasma, the relevant pharmacokinetic parameters and bioavailability. Results: the content determination of Vee Glenn Dean derivative YHX-13 in mouse plasma by HPLC method in good shape, can be completely separated from the internal standard, there is a linear relationship good in the range of 100~4000ng/mL, the correlation coefficient r=0.9993; intra day precision RSD in 7.2%~12.2% between day precision RSD in 8.6%~13.3%; the recovery was 96.7 ~106.65%, R SD 4.86~6.01%; stability at room temperature 24h and repeated freezing and thawing 5 times are good. Oral pharmacokinetic parameters: Cmax=1557.11ng/mL, Tmax=30min, AUC0~ - =358232ng - min/mL, AUC0~t=159898ng, min/mL, CL=41.8723mL/min/kg, t1/2=740.784min, MRT, =932.258min, Vss=39035.7mL/kg; intravenous pharmacokinetic parameters: Cmax=1610.22ng/mL, Tmax=3min, AUC0~ for =79203.6ng, min/mL, AUC0~t=66177.7ng, min/mL, CL=63.1284mL/min/kg, t1/2=101.103min, MRT=125.331min, Vss=7911.93mL/kg, bioavailability F 80.54%. conclusion: related conditions of the HPLC method for detecting sensitivity content in mouse plasma YHX-13, high accuracy, good repeatability, used in the pharmacokinetics of YHX-13 in mice, can get the relevant parameters and good bioavailability. The second chapter: vildagliptin. Study on the tissue distribution of biological YHX-13 in mice
Objective: to establish a method for determination of the HPLC method for the determination of YHX-13 in mice, investigate the distribution in tissues of mice. Methods: by intragastric administration of Kunming mice, respectively, in the absorption phase time distribution, phase time and eliminate the time points were decapitated, take out the corresponding time points of the organization the heart, liver, spleen, lung, kidney, brain, content of YHX-13 tissues and corresponding time points of measurement. Results: YHX-13 could be separated completely and the internal standard peak in mouse tissues homogenate, and no interference by endogenous substances in biological samples; there was a good linear relationship in the range of mL 100~4000ng/, correlation the coefficient of R was greater than 0.99 days; the precision of RSD is less than or equal to 11.01%, the inter day precision is less than 12.13% RSD; the recovery rate was 95.54%~104.31%, RSD to 3.2%~8.66%, can meet the requirements of detection in biological samples YHX-13 and 24h at room temperature and after 5 times of repeated freezing and thawing Conclusion: the HPLC method can accurately detect the content of YHX-13 in various tissues of mice. After gavage, YHX-13 is mainly distributed in the lungs, followed by the kidneys, and less distributed in the liver and spleen.

【学位授予单位】：重庆医科大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R969.1

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