本文關鍵詞： YHX-13 維格列汀 藥代動力學 組織分布　出處：《重慶醫(yī)科大學》2014年碩士論文　論文類型：學位論文

【摘要】：如今糖尿病患病率呈逐年上升的趨勢，已經成為繼腫瘤和心血管疾病之后，人類生命健康的第三大殺手。目前中國是全球范圍內糖尿病增長最快的地區(qū)，并將成為世界糖尿病第一大國，患病人群以II型糖尿病為主，所占比例達到了93.7％。DDP-IV抑制劑作為一類新的口服降糖藥物，應用于II型糖尿病的治療中，其對血糖控制良好的安全性、有效性以及耐受性已經在大量的臨床試驗與實際應用中得到了充分的證實。 維格列汀是一種高選擇性的DDP-IV底物抑制劑，通過與DDP-IV形成可逆的共價鍵而緊密結合，緩慢解離，解離時間達到了55min，因而可以更為強效的抑制DDP-IV活性。重慶醫(yī)科大學藥物化學實驗室通過對維格列汀結構的修飾，并進行體外活體篩選，得到了一系列維格列汀衍生物，，YHX-13是其中活性較好的衍生物之一。本實驗通過對YHX-13的藥代動力學及組織分布研究，可以考察該衍生物的藥理學相關性質，為新藥的研發(fā)提供理論依據。第一章：維格列汀衍生物YHX-13檢測方法的建立及藥代動力學研究 目的：建立了維格列汀衍生物YHX-13在小鼠血漿中的含量測定方法，研究了其在小鼠體內的藥代動力學規(guī)律。方法：通過灌胃和尾靜脈注射兩種方式給藥昆明小鼠，在相應時間點眼眶取血，采用MCX固相萃取法處理生物樣品，高效液相色譜法，以乙腈和磷酸二氫鉀（40:60）作為流動相，檢測小鼠血漿中YHX-13的含量，求得相關藥代動力學參數(shù)及生物利用度。結果：采用HPLC法測定維格列汀衍生物YHX-13在小鼠血漿中的含量，峰形良好，與內標能夠完全分離，在100~4000ng/mL范圍內有良好的線性關系，相關系數(shù)r=0.9993；日內精密度RSD在7.2%~12.2%之間，日間精密度RSD在8.6%~13.3%之間；回收率在96.7~106.65%之間，RSD在4.86~6.01%之間；室溫放置24h的穩(wěn)定性和反復凍融5次后的穩(wěn)定性均良好�？诜幋鷦恿W參數(shù)：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；尾靜脈注射藥代動力學參數(shù)：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為80.54%。結論：該HPLC法相關條件用于YHX-13在小鼠血漿中的含量檢測靈敏度好、準確性高、有較好的重復性，使用于YHX-13在小鼠體內的藥代動力學研究，能夠得到良好的相關參數(shù)和生物利用度。第二章：維格列汀衍生物YHX-13在小鼠體內的組織分布研究 目的：建立了HPLC法測定YHX-13在小鼠組織中的含量測定方法，考察了其在小鼠組織中的分布情況。方法：通過灌胃給藥昆明小鼠，分別于吸收相時間點、分布相時間點和消除相時間點斷頭處死，取出相應時間點的組織心、肝、脾、肺、腎、腦，測量相應時間點各組織中YHX-13的含量。結果：YHX-13在小鼠各組織勻漿液中能與內標峰完全分離，且不受到生物樣品中內源性雜質的干擾；在100~4000ng/mL范圍內有良好的線性關系，相關系數(shù)r均大于0.99；的日內精密度RSD≤11.01%，日間精密度RSD≤12.13%；回收率為95.54%~104.31%，RSD為3.2%~8.66%，均能滿足YHX-13在生物樣品中的檢測要求，且室溫放置24h和反復凍融5次后的穩(wěn)定性良好。結論：該HPLC法能夠準確測出YHX-13在小鼠各組織中的含量，經過灌胃給藥后，YHX-13主要分布于肺部，其次是腎，肝和脾中有較少分布。
[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.

【學位授予單位】：重慶醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R969.1

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