本文關(guān)鍵詞： 癲癇病 卡馬西平 基因多態(tài)性 代謝 血藥濃度 藥物耐受性　出處：《吉林大學(xué)》2015年碩士論文　論文類(lèi)型：學(xué)位論文

【摘要】：癲癇是一種常見(jiàn)的慢性神經(jīng)系統(tǒng)疾病，目前藥物治療是控制癲癇的主要手段�？R西平（carbamazepine，CBZ）是最常用的抗癲癇藥物之一，但在治療過(guò)程中存在血藥濃度個(gè)體差異大，，有效性和安全性難于預(yù)測(cè)的特點(diǎn)，約有1/3的患者出現(xiàn)藥物耐受性，因此需要監(jiān)測(cè)患者的血藥濃度，實(shí)行個(gè)體化治療。 大量的研究證實(shí)，藥物代謝酶，轉(zhuǎn)運(yùn)體和靶蛋白的基因多態(tài)性是導(dǎo)致不同個(gè)體間藥物反應(yīng)差異的主要因素�？R西平主要通過(guò)抑制興奮性電壓依賴性鈉通道，如Nav1.1,1.2（SCN1A,SCN2A）,穩(wěn)定神經(jīng)細(xì)胞膜和減少興奮性氨基酸-谷氨酸的釋放而發(fā)揮抗癲癇作用。在體內(nèi)它首先經(jīng)肝臟的細(xì)胞色素氧化酶P450酶(cytochrome p450,CYP450)3A4轉(zhuǎn)化為有活性的CBZ-10，11-環(huán)氧化物（CBZE），然后被微粒體環(huán)氧化物水解酶(microsomal epoxide hydrolase,EPHX1)代謝為無(wú)活性的CBZ-10,11二氫二醇（CBZD）從腎臟排出。其中細(xì)胞色素P450氧化還原酶(P450oxidoreductase,POR)是CYP450同工酶唯一的電子供體，協(xié)助CYP3A4完成催化活性。由ABCB1和ABCC2編碼的MDR1和MPR2是CBZ的細(xì)胞外排轉(zhuǎn)運(yùn)體，阻礙CBZ的腸吸收和通過(guò)血腦屏障。因此負(fù)責(zé)CBZ代謝、轉(zhuǎn)運(yùn)的酶或蛋白的基因多態(tài)性可能通過(guò)改變其功能影響CBZ在體內(nèi)的血藥濃度和療效。 本課題首先分析了在83名中國(guó)成年癲癇患者中CYP3A4*1G、EPHX1T337C/A416G、ABCC2-24CT/1249GA/3972CT和SCN1A IVS5-91GA基因多態(tài)性對(duì)CBZ血藥濃度和藥物耐受性的影響。結(jié)果表明攜帶變異的EPHX1A416G基因型的癲癇患者血清中CBZ濃度顯著地高于野生型基因的攜帶者（AG+GG vs AA, P=0.005）。攜帶EPHX1337TC/CC基因型的患者易產(chǎn)生藥物的耐受性（odds ratio≥4.0）。 進(jìn)一步我們分析了在210名中國(guó)兒童癲癇患者中CYP3A4*1G、POR*28和ABCB1C1236T、G2677T/A、C3435T基因多態(tài)性對(duì)CBZ及其代謝產(chǎn)物CBZE、CBZD的影響。結(jié)果表明與3435CT基因型攜帶者相比，攜帶3435CC基因型的患者具有較高的劑量調(diào)整的CBZ及其兩個(gè)代謝產(chǎn)物CBZE和CBZD濃度（P 0.05），CYP3A4*1G突變體攜帶者具有較低的劑量調(diào)整的CBZ和CBZE濃度。 以上數(shù)據(jù)表明CBZ的主要轉(zhuǎn)運(yùn)體和代謝酶的基因多態(tài)性是CBZ代謝的個(gè)體差異的影響因素之一，也是導(dǎo)致藥物產(chǎn)生耐受性的原因。這些結(jié)果將為CBZ實(shí)現(xiàn)個(gè)體化治療，增加藥物療效提供重要的理論依據(jù)。
[Abstract]:Epilepsy is a common chronic nervous system disease. At present, drug therapy is the main means to control epilepsy. Carbamazepine CBZ is one of the most commonly used antiepileptic drugs. However, in the course of treatment, there is a large individual difference in blood drug concentration, the effectiveness and safety of the characteristics of difficult to predict, about 1/3 patients have drug tolerance, so we need to monitor the blood drug concentration of patients. Individualized treatment was carried out. A large number of studies have confirmed that gene polymorphisms of drug metabolizing enzymes, transporters and target proteins are the main factors leading to the difference of drug reactions among individuals. Carbamazepine mainly inhibits excitatory voltage-dependent sodium channels. For example, Nav1.1 1. 1 + 1. 2% SCN1A (SCN2A). It plays an antiepileptic effect by stabilizing the membrane of nerve cells and reducing the release of excitatory amino acid-glutamic acid. In vivo, it first passes through the cytochrome oxidase P450 enzyme of the liver. Cytochrome p450. CYP450)3A4 was transformed into active CBZ-10O11-epoxide (CBZE). Then the microsomal epoxide hydrolase EPHX1 was metabolized into inactive CBZ-10. The cytochrome P450 redox enzyme P450 oxidoreductase was excreted from the kidney. POR) is the only electron donor of CYP450 isozyme. MDR1 and MPR2 encoded by ABCB1 and ABCC2 are the extracellular efflux transporters of CBZ. Therefore, gene polymorphisms of enzymes or proteins responsible for CBZ metabolism and transport may affect the concentration and efficacy of CBZ in vivo by altering its function. In this study, we first analyzed the CYP3A41G EPHX1T337C / A416G in 83 Chinese adult epileptic patients. ABCC2-24CT/1249GA/3972CT and SCN1A. The effect of IVS5-91GA gene polymorphism on serum drug concentration and drug tolerance of CBZ. The results showed that the serum CBZ concentration in epileptic patients with variant EPHX1A416G genotype was significant. Carriers with higher than wild-type genes (. AG GG vs AA. Patients with EPHX1337TC/CC genotype were likely to develop drug tolerance and odds of ratio 鈮

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