本文關(guān)鍵詞： CYP2C9 蛇床子素 基因多態(tài)性　出處：《重慶醫(yī)科大學(xué)》2014年碩士論文　論文類(lèi)型：學(xué)位論文

【摘要】：蛇床子素是存在于多種中藥中的藥理活性成分，具有廣泛的藥理作用，在臨床應(yīng)用前景廣闊，是一個(gè)極具開(kāi)發(fā)利用價(jià)值的藥理活性成分。目前，國(guó)內(nèi)外對(duì)蛇床子素藥理藥效方面的研究較多，而關(guān)于蛇床子素藥物代謝動(dòng)力學(xué)相關(guān)研究較少，本文了針對(duì)蛇床子素代謝的過(guò)程，考察其對(duì)藥物代謝酶CYP2C9的作用，為蛇床子素的開(kāi)發(fā)應(yīng)用提供參考。 CYP2C9是在人群中存在基因多態(tài)性，常見(jiàn)基因型為CYP2C9*1、CYP2C9*2、CYP2C9*3。與CYP2C9*1相比，突變型的CYP2C9*2、CYP2C9*3酶代謝能力降低，，但對(duì)藥物的反應(yīng)靈敏性增加，更易受到藥物的誘導(dǎo)或抑制，進(jìn)一步使酶代謝藥物的能力降低，從而導(dǎo)致藥物不良反應(yīng)的發(fā)生。因此，考察蛇床子素對(duì)不同基因型的CYP2C9酶的作用，對(duì)不同患者間的安全用藥具有重要意義。本文從體外初步評(píng)價(jià)了蛇床子素對(duì)CYP2C9*1、CYP2C9*2、CYP2C9*3酶的作用及作用機(jī)制，發(fā)現(xiàn)蛇床子素抑制CYP2C9*1、CYP2C9*2、CYP2C9*3酶活性，且抑制作用表現(xiàn)為：CYP2C9*3CYP2C9*2CYP2C9*1，抑制參數(shù)分別為Ki=21.93μM（CYP2C9*1）、Ki=18.10μM（CYP2C9*2）、Ki=13.12μM（CYP2C9*3）。表明蛇床子素對(duì)CYP2C9酶的抑制作用存在個(gè)體差異。 CYP2C9在不同種屬間的表達(dá)或酶活性高低存在差異，為了明確蛇床子素在混合微粒體中對(duì)CYP2C9酶的作用，本文同時(shí)考察了蛇床子對(duì)大鼠和人的混合肝微粒體中CYP2C9酶的作用。發(fā)現(xiàn)蛇床子素對(duì)兩者中CYP2C9酶均具有抑制作用，且種屬差異明顯：對(duì)大鼠肝中CYP2C9酶呈競(jìng)爭(zhēng)性抑制，而在人肝中呈非競(jìng)爭(zhēng)性抑制；且在大鼠肝體系中的抑制作用（Ki=8.187μM）顯著大于人肝體系中的抑制作用（Ki=49.81μM）。 藥物在體內(nèi)需經(jīng)復(fù)雜的轉(zhuǎn)化過(guò)程，因此，藥物對(duì)酶的作用不能簡(jiǎn)單地從體外實(shí)驗(yàn)結(jié)果斷定，需進(jìn)一步進(jìn)行體內(nèi)驗(yàn)證。本文選用主要經(jīng)CYP2C9代謝的吲哚美辛，與蛇床子素聯(lián)合給藥于大鼠后，給藥組與對(duì)照組藥動(dòng)學(xué)參數(shù)比較發(fā)現(xiàn)：吲哚美辛的AUC、Cmax、CL/F不變，Tmax、T1/2延長(zhǎng)，其表明蛇床子素對(duì)吲哚美辛的體內(nèi)藥動(dòng)學(xué)過(guò)程存在影響，但對(duì)CYP2C9介導(dǎo)的代謝過(guò)程無(wú)作用。由于體外和體內(nèi)實(shí)驗(yàn)的差異性，其蛇床子素對(duì)吲哚美辛體內(nèi)其他過(guò)程的作用需進(jìn)一步研究明確。 本文通過(guò)體外、體內(nèi)研究了蛇床子素對(duì)CYP2C9酶的抑制作用，并發(fā)現(xiàn)個(gè)體差異和種屬差異的影響。結(jié)果提示在蛇床子素實(shí)驗(yàn)研究和臨床使用中，需注意個(gè)體差異和種屬差異產(chǎn)生的影響。蛇床子素影響吲哚美辛的體內(nèi)藥動(dòng)過(guò)程，因而在臨床用藥時(shí)，尤其注意基因型為CYP2C9*2、CYP2C9*3的患者使用藥物的風(fēng)險(xiǎn)，減少藥物不良反應(yīng)，并避免與其他藥物發(fā)生相互作用，保證臨床安全合理用藥。
[Abstract]:Osthol is a kind of pharmacological active component which exists in many kinds of traditional Chinese medicine. It has extensive pharmacological effect and has a broad prospect in clinical application. It is a pharmacological active component with great value of development and utilization. There are many studies on the pharmacological effects of osthol at home and abroad, but there are few studies on the pharmacokinetics of osthol. In this paper, the effects of osthol on the metabolism of osthol CYP2C9 were investigated. It provides a reference for the development and application of osthol. The common genotype of CYP2C9 is CYP2C9C9O2CYP2C9O2CYP2C9O33.Compared with CYP2C9*1, the metabolic ability of mutant CYP2C9O2CYP2C9t3 is decreased, but its sensitivity to drugs is increased, and it is more susceptible to drug induction or inhibition. The ability of metabolizing drugs was further reduced, which led to the occurrence of adverse drug reactions. Therefore, the effects of osthol on CYP2C9 enzymes of different genotypes were investigated. In this paper, the effect and mechanism of osthol on CYP2C9O2-CYP2C9O3-CYP2C9O3-CYP2C91-CYP2C91-CYP2C91-CYP2C93-CYP2C93-was evaluated in vitro, and it was found that osthol inhibited the activity of CYP2C9O2-CYP2C93. The inhibitory effects were as follows: 1: CYP2C9, 3CYP2C9, 2CYP2C9, and the inhibitory parameters were Ki=21.93 渭 M9, CYP2C9, CYP2C9 / 1, respectively. The inhibitory effect of osthol on CYP2C9 enzyme was different in individuals, and the inhibitory effect of CYP2C9 / 2 was 13.12 渭 MCYP2C9 / 1, which indicated that the inhibitory effect of osthol on CYP2C9 was different in individuals. In order to clarify the effect of osthol on CYP2C9 enzyme in mixed microsomes, the expression or enzyme activity of CYP2C9 was different among different species. The effects of osthol on CYP2C9 enzyme in rat and human liver microsomes were also investigated. It was found that osthol could inhibit CYP2C9 enzyme in both of them, and the difference of species was significant: the inhibition of CYP2C9 enzyme in rat liver was competitive. The inhibitory effect in rat liver system was 8.187 渭 M), and the inhibitory effect in human liver system was significantly higher than that in human liver system (49.81 渭 M-1). The drug needs complex transformation process in vivo. Therefore, the effect of drugs on enzyme can not be simply determined from the results of in vitro experiments, and should be further verified in vivo. In this paper, indomethacin, which is mainly metabolized by CYP2C9, is selected. The pharmacokinetic parameters of indomethacin group and control group were compared with those of control group. The results showed that the CLF of indolomethacin was prolonged, which indicated that osthol had an effect on the pharmacokinetic process of indomethacin in vivo, and the effect of osthol on the pharmacokinetic process of indomethacin in vivo was observed. Because of the difference between in vitro and in vivo experiments, the effect of osthol on other processes of indomethacin in vivo should be further studied. The inhibitory effect of osthol on CYP2C9 enzyme was studied in vitro, and the effects of individual and species differences were found. Attention should be paid to the effects of individual and species differences. Osthol affects the pharmacokinetics of indomethacin in vivo. Therefore, in clinical use, particular attention is paid to the risk of drug use in patients with genotypes CYP2C9 and CYP2C9, so as to reduce adverse drug reactions. And avoid the interaction with other drugs to ensure clinical safety and rational use.
【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(lèi)號(hào)】：R969.1

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