| 摘要: | 在鴉片類的藥物戒癮治療中，目前還是以美沙冬替代療法最為廣泛使用。但是基於美沙冬的劑量與個體差異的關係，在治療上還是存在著許多問題。本研究主要希望可以透過研究美沙冬藥物相關基因的多型性與單倍體型（haplotype）基因分析的方式來了解這些基因與美沙冬劑量之間的關係。
本研究經過中國附醫人體試驗委員會審核通過之後，收集了300位受試者的資料進行分析，並將受試者依其服用劑量的大小分為低劑量、中劑量與高劑量三個族群。並收集約100位身體健康且無使用鴉片類藥物成癮紀錄的受試者作為對照組。
與美沙冬相關的基因方面，以藥物動力學的角度探討了ABCB1、CYP2B6與NR1I2；以藥效學的角度則研究了OPRM1、DRD2、ANKK1與GNB3等基因，透過聚合酶連鎖反應技術去分析基因表現的情形與服用劑量之間的關聯性。經過統計的結果顯示在ABCB1基因上的rs1045642（3435C>T）此位點發生變異時，高劑量與低劑量相比，病人傾向使用高劑量（p<0.0001; OR=0.388; 95% CI=0.251-0.602）；CYP2B6基因上的rs3745274（516G>T）此位點發生變異時，高劑量與低劑量相比，則較傾向使用低劑量（p<0.0001; OR=3.190; 95% CI=1.906-5.337），中劑量與低劑量相比同樣較傾向使用低劑量（p<0.0001; OR=2.622; 95% CI=1.753-3.960）；DRD2基因上的rs1799978（-214A>G）、rs6275（939C>T）這些位點位點變異時，高劑量與低劑量相比較傾向於使用高劑量（rs1799978：p=0.002; OR=0.399; 95% CI=0.225-0.707；rs6275：p=0.001; OR=0.492; 95% CI=0.319-0.758）；而OPRM1基因上的rs1799971（118A>G） 與位點變異時，高劑量與低劑量相比時較傾向使用高劑量（p=0.014; OR=0.562; 95% CI=0.356-0.888）。在單倍體基因型分析方面當ABCB1基因上的rs1128503 C>T-rs1045642 C>T-rs2032582 G>T/A三個位點的基因型為CTG時，高劑量與低劑量相比較傾向使用高劑量（p=0.007; OR=33.0; 95% CI=2.568-423.99）。CYP 2B6基因上的rs3745274 G>T-rs2279343 A>G兩個位點的基因型為GA或GG時，高劑量與低劑量相比，較傾向使用高劑量（GA：p＝0.0004; OR=3.028; 95% CI=1.639-5.593；GG：p=0.024; OR=2.5; 95% CI=1.128-5.539），中劑量與低劑量相比時，亦較傾向使用相對較高的中劑量（GA：p<0.0001; OR=2.868; 95% CI=1.192-4.778；GG：p=0.0035; OR=2.705; 95% CI=1.386-5.278）。而ANKK1與DRD2基因上五個位點rs1800497 C>T-rs4648317 C>T-rs1799978 A>G-rs1076560 C>A-rs6275 C>T基因型為CCGAC時高劑量與低劑量相比，較傾向使用低劑量（p<0.0001; OR=0.004; 95% CI=0.001-0.053）。
透過本研究發現藥物基因體學提供了一個有效的方法來探討美沙冬的藥物劑量，本研究也證實在部份位點產生的基因多型性對於在決定美沙冬戒癮治療中因為個體差異所造成的劑量判斷有個合適的依據。
The most common treatment for opioid dependence is substitution therapy with methadone, and the dosage of methadone is individualized. The aim of the present study is to identify whether the single nucleotide polymorphisms (SNP) or haplotypes in related genes associated with response to methadone maintenance treatment (MMT) and dosage requirement of methadone.
After signed the informed consents, approximately 300 subjects were recruited and allocated into three groups according to their stabilized daily dose of methadone: the first group was comprised of subjects stabilized on a lower dose, the second group comprised of subjects stabilized at a medium dose, and the last group comprised of subjects stabilized at a higher dose. The decision to split the groups at a methadone dose was based on the major maintained dose of patients. The control group was healthy volunteers with no lifetime history of heroin dependence. In this study, there are 15 SNPs detected by real-time polymerase chain reaction with 5'-nuclease allele discrimination assays (ABI PRISM 7900 land) and restriction fragment length polymorphism (RFLP) assay in ABCB1, NR1I2, CYP2B6 genes (pharmacokinetics) and in OPRM1, DRD2, ANKK1, GNB3 genes (pharmacodynamics). As results, the maximum daily methadone doses were significantly assoiated with the ABCB1 rs1045642C>T, CYP 2B6 rs3745274G>T, OPRM1 rs1799971A>G, DRD2 rs1799978C>T and rs6275A>G SNPs. Carriers of the variant rs1799971G alleles required higher methadone doses than noncarriers. In addition, the subjects carried the CCGAC haplotype of ANKK1 rs1800497C>T, DRD2 rs4648317C>T, rs1799978 A>G, rs1076560 C>A, rs6275 C>T required significant lower dose than TTGAT haplotype (p<0.0001; OR=0.004; 95% CI=0.001-0.053).
Pharmacogenetics has great potential for improving treatment outcome as we identify gene variants and polymorphism is recognized as important determinants of interindividual variability in methadone pharmacokinetics and pharmacodynamics. |
