美沙冬維持治療：從基因到機轉之探討

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題名:	美沙冬維持治療：從基因到機轉之探討
作者:	洪靚娟(Chin-Chuan Hung);黃介良(Chieh-Liang Huang);林宜慧(Yi-Hui Lin);劉宏輝
貢獻者:	藥學院藥學系;中國附醫藥劑部
日期:	2012-07-31
上傳時間:	2012-06-15 11:41:38 (UTC+8)
摘要:	海?因成癮是一個重要的社會及醫?上的問題，但是對於此一成癮性疾病之有效治?卻很有限。美沙冬維持治?是目前最常用且有效的?法，使長期使用短效型鴉片成癮患者能夠回??常之生?現象。然而，美沙冬治?之個體差?大且其治?範圍狹窄，因此，影響美沙冬代謝之酵素、轉運子（P- 醣蛋白）及μ-鴉片受體之基因多型性位點可能在美沙冬治?之藥物動?學及藥效學個體間差?上扮演重要的角色。在藥物動?學方面，CYP2B6 為美沙冬代謝途徑中重要的酵素。而CYP2B6 基因已被證實在C64T，G516T，C777A，A785G 和C1459T 位點的基因多型性會造成胺基酸取代的現象，進而造成蛋白質結構的改變。至於轉運子P-醣蛋白，具有多個基因多型性位點，像是A61G，G1199A， C1236T，G2677T/A 和C3435T，顯示出與運輸功能的改變有關?性。而在藥效學方面，由OPRM1 轉譯的μ-鴉片受體為美沙冬藥?作用之主要受體，?質性變? 118A>G 會?低一些鴉片?藥物(包含美沙冬)的效?，雖然它對鍵結親和?以及一些鴉片受體致效劑受體的效?是有爭議的。另一方面，中腦邊緣多巴胺?與的回饋現象使得多巴胺受體成為藥物服用和成癮研究中的重要目標。研究指出 DRD2 957C>T 基因多型性與美沙冬維持治?和劑?是相關的。但是，這方面的關?性並未在其他研究中發現，取而代之的是DRD2 957C>T 基因多型性位點與美沙冬每日的平均和最大劑?間具有顯著的相關性。一些研究也評估ABCB1 和OPRM1 基因上?同的單一核?酸多型性會對美沙冬的使用劑 ?造成影響。然而，這些矛盾的結果表示，進?全面詳盡的藥物基因體學研究是非常重要的，能夠進一步闡述基因是否會對美沙冬維持治?和所需劑?產生影響。再者，這些有可能會影響美沙冬維持治 ?的基因多型性位點，其分子機轉仍尚待發掘。綜合上述，本研究的目標為：(1)評估CYP2B6 基因多型性對美沙冬維持治?的反應和美沙冬劑? 以及血中濃?的影響。(2)評估ABCB1 及上游NR1I2 基因多型性對美沙冬維持治?的反應和美沙冬劑?以及血中濃?的影響。(3)研究OPRM1 基因多型性與美沙冬維持治?的反應和美沙冬劑?和美沙冬劑?以及血中濃?之間的相關性。(4)藉由分析全面的基因位點，從DRD2 啟動子到ANKK1 的基因多型性，?解釋DRD2 和ANKK1 的單一核?酸多型性在美沙冬維持治?的反應和美沙冬使用劑 ?方面所扮演的重要性。(5)基於藥物動?學和藥效學的基因考?，發展一個可預測美沙冬維持治? 的反應以及美沙冬使用劑?的模式，並提供美沙冬維持治?的個人化藥物治?。(6)研究美沙冬和Pgp 間相互作用的分子機轉以及ABCB1 上的單一核?酸多型性對此相互作用的影響。(7)探?OPRM1、 DRD2 和ANKK1 單一核?酸多型性對美沙冬劑?需求造成的影響的分子機轉。本研究之結果將能夠提供有關藥物基因體學和美沙冬維持治?的?同個體差?性完整的?解，且在?床上為病人提供?好的治?。 Opiate addiction is a major social and medical problem that imposes a significant burden on society. Despite the size and scope of theses problems, there are few effective treatments for this addiction. Methadone maintenance is an effective and most widely used treatment for opiate addiction, allowing normalization of many physiological abnormalities caused by chronic use of short-acting opiates. It has a large interindividual variability in response and a narrow therapeutic index. Genetic polymorphisms in genes coding for methadone-metabolizing enzymes, transporter proteins (p-glycoprotein; P-gp), and μ-opioid receptors may explain the observed interindividual variation in the pharmacokinetics and pharmacogynamics of methadone. In the metabolic pathway of methadone, CYP2B6 has been demonstrated to be an important enzyme. It has been identified in the CYP2B6 gene that C64T, G516T, C777A, A785G, and C1459T polymorphisms would result in amino acid substitutions. As for the transporter protein, P-gp, several genetic polymorphisms were demonstrated to be associated with altered transport function, such as A61G, G1199A, C1236T, G2677A/T and C3435T. In the pharmacodynamic aspect, the μ-opioid receptor, encoded by the μ-opioid receptor gene (OPRM1), is the pharmacological target of methadone. The nonsynonymous 118A>G has been associated with a decreased potency of several opioids, including methadone, even though its impact on the binding affinity and potency of several opioid receptors agonists is controversial. On the other hand, involvement of the mesolimbic dopamine in reward phenomenon makes each dopamine receptor an important target for the study of drug taking and addiction. It has been demonstrated that DRD2 957C>T polymorphism was associated with response to MMT and methadone dosing. However, this association was not detected by another study, in stead, they found that DRD2 939C>T polymorphism was significantly associated with the average and maximum daily methadone doses. Several studies have also evaluated the effect of different SNPs in ABCB1 and OPRM1 gene on the dosage requirement of methadone. Nevertheless, the conflicting results demonstrated the importance of conducting a comprehensive pharmacogenomic study to elucidate whether genetic factors influence the response to MMT and the dosage requirement of methadone. Furthermore, the molecular mechanisms of how these genetic polymorphisms may affect response to MMT are also important issues that are still undiscovered. Taken together, the objectives of the present study are: (1) Assess the impact of CYP2B6 genetic polymorphisms on the response of MMT and methadone dosage requirement and plasma concentration. (2) Evaluate the effect of ABCB1 and the upstream NR1I2 genetic polymorphisms on the response of MMT and methadone dosage requirement and plasma concentration. (3) Investigate the association between OPRM1 genetic polymorphisms and response to MMT and the influence on methadone dosage requirement and plasma concentration. (4) By analysis spanning the whole gene locus, from the DRD2 promoter to the ANKK1 genetic polymorphisms, to elucidate the role of DRD2 and ANKK1 SNPs played in the response to MMT and the dosage requirement of methadone. (5) Develop a predictive model of response to MMT and methadone dosage requirement based on the pharmacokinetic and pharmacodynamic genetic factors and provide an individualized pharmacotherapy of MMT. (6) Investigate the underlying mechanisms of the interaction between methadone and Pgp and the effect of SNPs in ABCB1 gene on this interaction. (7) Explore the molecular mechanisms underlying the influence of OPRM1, DRD2 and ANKK1 SNPs on the methadone dosage requirement. Results from the present study shall provide a complete understanding of the pharmacogenomics and mechanisms of interindividual variations of MMT and shed light on the better treatment design for patients.
顯示於類別:	[中國藥學暨中藥資源學系暨碩博班] 研究計畫

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