本文選題：氯唑沙宗 + HPLC-PDA-ESI-ITMS~n�。� 參考：《福建中醫(yī)藥大學(xué)》2014年碩士論文

【摘要】：氯唑沙宗(chlorzoxazone)的化學(xué)名為5-氯-2-苯并惡唑酮(5-chloro-2-Hydroxy-benzoxazole),是一種口服中樞性肌肉松弛劑,作用快且持久,可有效緩解各種急慢性扭傷、挫傷、肌肉勞損等引起的軟組織疼痛以及中樞神經(jīng)引起的肌肉痙攣疼痛。氯唑沙宗作用于脊髓反射中樞,能夠阻斷連接知覺神經(jīng)和運(yùn)動(dòng)神經(jīng)的介在神經(jīng)元。由于多突觸反射的抑制,使反射興奮低下而緩解骨骼肌緊張。另外氯唑沙宗常常用于評(píng)價(jià)肝臟微粒體細(xì)胞色素CYP2EI酶活性,作為其唯一的特異性探針底物,氯唑沙宗在人體內(nèi)主要經(jīng)羥基化代謝為6-羥基氯唑沙宗,根據(jù)6-羥基氯唑沙宗與氯唑沙宗的血藥濃度比值或尿中6-羥基氯唑沙宗的回收率可反應(yīng)CYP2EI的酶活性。 實(shí)驗(yàn)第一部分通過采用HPLC-PDA-ESI-ITMS"聯(lián)用技術(shù),分離并鑒定出SD大鼠口服氯唑沙宗原料藥后,尿液中的5種氯唑沙宗代謝產(chǎn)物,分別為6-羥基氯唑沙宗、6-羥基氯唑沙宗葡萄糖醛酸軛合物、6-羥基氯唑沙宗硫酸酯軛合物、氯唑沙宗葡萄糖醛酸軛合物和氯唑沙宗硫酸酯軛合物,同時(shí)揭示了這5種代謝產(chǎn)物的質(zhì)譜裂解規(guī)律。實(shí)驗(yàn)發(fā)現(xiàn)6-羥基氯唑沙宗葡萄糖醛酸軛合物和6-羥基氯唑沙宗硫酸酯軛合物為主要代謝產(chǎn)物,可以經(jīng)過水解酶的作用得到6-羥基氯唑沙宗,所以實(shí)驗(yàn)第二部分設(shè)計(jì)了一套方案,獲取6-羥基氯唑沙宗葡萄糖醛酸軛合物和6-羥基氯唑沙宗硫酸酯軛合物這兩個(gè)目標(biāo)代謝產(chǎn)物。 實(shí)驗(yàn)第二部分我們通過給SD大鼠灌胃一定劑量的氯唑沙宗原料藥后,收集其尿液。采用上樣過D-101大孔樹脂方法去除尿液中的部分雜質(zhì),得到一系列洗脫流份。與此同時(shí)結(jié)合高效液相色譜儀的高效分離檢測(cè)手段,檢測(cè)樣品,合并含有相同代謝產(chǎn)物的流份,得到一定純度的代謝產(chǎn)物粗提物。然后采用半制備型高效液相色譜儀對(duì)已經(jīng)得到的代謝產(chǎn)物粗提物進(jìn)行分離制備,從而得到所需的目標(biāo)代謝產(chǎn)物。最后對(duì)所制備得到的目標(biāo)代謝產(chǎn)物進(jìn)行含量純度測(cè)定檢驗(yàn)和質(zhì)譜結(jié)構(gòu)確證。 第三部分,我們考察了臨床上常用復(fù)方氯唑沙宗片中的兩主成分氯唑沙宗和對(duì)乙酰氨基酚在SD大鼠體內(nèi)聯(lián)合用藥的藥動(dòng)學(xué)行為進(jìn)行了初步探討,為臨床合理用藥提供了指導(dǎo)。實(shí)驗(yàn)結(jié)果發(fā)現(xiàn)與單獨(dú)用藥相比,聯(lián)合用藥后,對(duì)乙酰氨基酚的達(dá)峰濃度顯著降低、平均滯留時(shí)間有所增加。氯唑沙宗的半衰期有所增加。
[Abstract]:Chlorzoxazone (Chlorzoxazone) is an oral central muscle relaxant called 5-chloro-2-Hydroxy-benzoxazoleone. It has a fast and lasting effect on relieving all kinds of acute and chronic sprain and contusion. Soft tissue pain caused by muscle strain and muscle spasm caused by central nervous system. Clozoxazone acts on the spinal reflex center and blocks the mediators connecting the perceptual and motor nerves. Because of the inhibition of polysynaptic reflex, the reflex is low and the skeletal muscle tension is alleviated. In addition, chlorzoxazone is often used to evaluate the activity of liver microsomal cytochrome CYP2EI. As its only specific probe substrate, clozoxazone is mainly metabolized by hydroxylation to 6-hydroxychlorazolazone in human body. The activity of CYP2EI can be reflected by the ratio of 6-hydroxyclozoxazone to clozoxazone in blood or the recovery rate of 6-hydroxyclozoxazone in urine. The first part of the experiment used HPLC-PDA-ESI-ITMS to isolate and identify five chlorzoxazone metabolites in urine after oral clozoxazone in SD rats. They are 6-hydroxyclozoxazole-6-hydroxychloroxazole-glucuronic acid yoke, chlorzoxazone glucuronic acid conjugate and chlorzoxazolone sulfate yoke, respectively. At the same time, the law of mass spectrometry cleavage of the five metabolites was revealed. It was found that 6-hydroxyclozoxazone glucuronic acid conjugate and 6-hydroxyclozoxazone sulfate conjugate were the main metabolites, and 6-hydroxychlorazolazone could be obtained by hydrolase. Therefore, a set of schemes was designed in the second part of the experiment. Two target metabolites of 6-hydroxyclozoxazone glucuronic acid conjugate and 6-hydroxyclozoxazone sulfate conjugate were obtained. In the second part of the experiment, we collected the urine of SD rats by intragastric administration of clozoxazone. A series of elution fractions were obtained by using D-101 macroporous resin to remove some impurities in urine. At the same time, combined with the high performance liquid chromatograph, the sample was detected, combined with the same metabolites of the flow, a certain purity of the crude extract of metabolites was obtained. Then the crude extracts of metabolites were separated and prepared by semi-preparation high performance liquid chromatograph (HPLC), and the desired metabolites were obtained. Finally, the content purity of the target metabolites was determined and the structure of the target metabolites was confirmed by mass spectrometry. In the third part, we investigated the pharmacokinetic behavior of acetaminophen combined with chlorzoxazone Zong He, which is commonly used in clinical compound chlorzoxazone tablets in SD rats, and provided guidance for rational use of acetaminophen in clinic. The results showed that the peak concentration of acetaminophen was significantly decreased and the mean residence time was increased. The half-life of chlorzoxazone increased.
【學(xué)位授予單位】：福建中醫(yī)藥大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R965

【參考文獻(xiàn)】

相關(guān)期刊論文 前10條

1 宋立中;石慶平;李見春;;復(fù)方氯唑沙宗膠囊人體藥物動(dòng)力學(xué)研究[J];安徽醫(yī)藥;2006年09期

2 陳懷俠;杜鵬;韓鳳梅;陳勇;;液相色譜-串聯(lián)質(zhì)譜法分析樟柳堿大鼠肝勻漿代謝產(chǎn)物[J];分析化學(xué);2006年12期

3 戴海學(xué);李曉蓉;李宇航;劉蘊(yùn);薛明;;丹參酮ⅡA和丹參酮Ⅰ的電子轟擊與電噴霧電離質(zhì)譜分析[J];分析試驗(yàn)室;2008年05期

4 劉萍,蔣明波,翟浦英,王梅,賈正民,趙靜;復(fù)方氯唑沙宗的藥理和臨床應(yīng)用[J];河北醫(yī)藥;1998年05期

5 杜玲,崔文海;對(duì)復(fù)方氯唑沙宗片含量的HPLC法測(cè)定中流動(dòng)相配比的改進(jìn)[J];山東醫(yī)藥工業(yè);2001年03期

6 胡增峰;黃榮清;肖炳坤;楊建云;;高效液相色譜法制備大鼠體內(nèi)5-甲氧色胺衍生物(5-MT)的代謝產(chǎn)物[J];現(xiàn)代科學(xué)儀器;2008年05期

7 楊琳;郭曉宇;王齊放;陳穎;車亦馨;車慶明;;大鼠血清中黃芩素代謝產(chǎn)物的鑒定(英文)[J];Journal of Chinese Pharmaceutical Sciences;2011年03期

8 杜宗敏,黃海華,陳笑艷,鐘大放;人尿中苯丙哌林羥基化代謝產(chǎn)物的研究[J];藥學(xué)學(xué)報(bào);2000年12期

9 丁黎,張正行,倪沛洲,王廣基,安登魁;LC/DAD/MSD技術(shù)研究大鼠服藥膽汁中鹽酸非洛普I相代謝產(chǎn)物[J];藥學(xué)學(xué)報(bào);2001年03期

10 陳懷俠;沈少林;韓鳳梅;陳勇;;高效液相色譜-電噴霧離子阱串聯(lián)質(zhì)譜分析水蘇堿及其大鼠體內(nèi)代謝物[J];藥學(xué)學(xué)報(bào);2006年05期

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