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

【摘要】：如今糖尿病患病率呈逐年上升的趨勢(shì)，已經(jīng)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(guó)是全球范圍內(nèi)糖尿病增長(zhǎng)最快的地區(qū)，并將成為世界糖尿病第一大國(guó)，患病人群以II型糖尿病為主，所占比例達(dá)到了93.7％。DDP-IV抑制劑作為一類新的口服降糖藥物，應(yīng)用于II型糖尿病的治療中，其對(duì)血糖控制良好的安全性、有效性以及耐受性已經(jīng)在大量的臨床試驗(yàn)與實(shí)際應(yīng)用中得到了充分的證實(shí)。 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(jià)鍵而緊密結(jié)合，緩慢解離，解離時(shí)間達(dá)到了55min，因而可以更為強(qiáng)效的抑制DDP-IV活性。重慶醫(yī)科大學(xué)藥物化學(xué)實(shí)驗(yàn)室通過對(duì)維格列汀結(jié)構(gòu)的修飾，并進(jìn)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(shí)驗(yàn)通過對(duì)YHX-13的藥代動(dòng)力學(xué)及組織分布研究，可以考察該衍生物的藥理學(xué)相關(guān)性質(zhì)，為新藥的研發(fā)提供理論依據(jù)。第一章：維格列汀衍生物YHX-13檢測(cè)方法的建立及藥代動(dòng)力學(xué)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(cè)定方法，研究了其在小鼠體內(nèi)的藥代動(dòng)力學(xué)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(yīng)時(shí)間點(diǎn)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(dòng)相，檢測(cè)小鼠血漿中YHX-13的含量，求得相關(guān)藥代動(dòng)力學(xué)參數(shù)及生物利用度。結(jié)果：采用HPLC法測(cè)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(nèi)標(biāo)能夠完全分離，在100~4000ng/mL范圍內(nèi)有良好的線性關(guān)系，相關(guān)系數(shù)r=0.9993；日內(nèi)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(fù)凍融5次后的穩(wěn)定性均良好�？诜幋鷦�(dòng)力學(xué)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(dòng)力學(xué)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(jié)論：該HPLC法相關(guān)條件用于YHX-13在小鼠血漿中的含量檢測(cè)靈敏度好、準(zhǔn)確性高、有較好的重復(fù)性，使用于YHX-13在小鼠體內(nèi)的藥代動(dòng)力學(xué)研究，能夠得到良好的相關(guān)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(nèi)的組織分布研究 目的：建立了HPLC法測(cè)定YHX-13在小鼠組織中的含量測(cè)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(shí)間點(diǎn)、分布相時(shí)間點(diǎn)和消除相時(shí)間點(diǎn)斷頭處死，取出相應(yīng)時(shí)間點(diǎn)的組織心、肝、脾、肺、腎、腦，測(cè)量相應(yīng)時(shí)間點(diǎn)各組織中YHX-13的含量。結(jié)果：YHX-13在小鼠各組織勻漿液中能與內(nèi)標(biāo)峰完全分離，且不受到生物樣品中內(nèi)源性雜質(zhì)的干擾；在100~4000ng/mL范圍內(nèi)有良好的線性關(guān)系，相關(guān)系數(shù)r均大于0.99；的日內(nèi)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(cè)要求，且室溫放置24h和反復(fù)凍融5次后的穩(wěn)定性良好。結(jié)論：該HPLC法能夠準(zhǔn)確測(cè)出YHX-13在小鼠各組織中的含量，經(jīng)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(xué)位授予單位】：重慶醫(yī)科大學(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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