Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan.
Pharmacogenomics. 2011 Nov;12(11):1525-33. doi: 10.2217/pgs.11.96. Epub 2011 Sep 8.
The present study explored the integrative effect of genes encoding methadone pharmacokinetic and pharmacodynamic pathways on methadone maintenance doses in Han Chinese Patients.
MATERIALS & METHODS: Genomic DNA was extracted from 321 opioid-dependent patients and 202 healthy controls, and realtime-PCR and PCR-RFLP were conducted to determine the genotypes.
Pair-wise comparisons revealed that carriers of the variants ABCB1 3435C>T or CYP2B6 516G>T alleles were more likely to require a higher methadone dose than noncarriers (both p < 0.0001). On the other hand, carriers of the variant DRD2 -214A>G or 939C>T allele had a twofold chance of requiring a lower methadone dose than noncarriers (p = 0.001). Proportional odds regression with adjustment of cofactors demonstrated that ABCB1, CYP2B6, OPRM1, ANKK1 and DRD2 genetic variants were jointly correlated with optimal methadone dose (adjusted r(2) = 53%).
These findings provide new insight to the fact that the interindividual variability of methadone dosage requirement is polygenetic and cannot be explained by a single-gene effect.
本研究旨在探讨编码美沙酮药代动力学和药效学途径的基因与美沙酮维持剂量在汉族患者中的综合作用。
从 321 名阿片类药物依赖患者和 202 名健康对照者中提取基因组 DNA，采用实时 PCR 和 PCR-RFLP 方法确定基因型。
两两比较显示，ABCB1 3435C>T 或 CYP2B6 516G>T 变异等位基因的携带者比非携带者更有可能需要更高的美沙酮剂量（均 p<0.0001）。另一方面，DRD2-214A>G 或 939C>T 变异等位基因的携带者比非携带者需要更低剂量美沙酮的可能性增加了一倍（p=0.001）。在调整协变量后进行比例优势回归分析表明，ABCB1、CYP2B6、OPRM1、ANKK1 和 DRD2 基因变异与美沙酮的最佳剂量呈相关性（调整 r(2)=53%）。
这些发现为美沙酮剂量需求的个体间变异性是多基因的，不能用单个基因效应来解释这一事实提供了新的认识。
