ABCB1 (MDR1) genetic variants are associated with methadone doses required for effective treatment of heroin dependence
ABCB1 (MDR1) genetic variants are associated with methadone doses required for effective treatment of heroin dependence
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DOI：
10.1093/hmg/ddn122
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发表时间：
2008-07-15
影响因子：
3.5
通讯作者：
Kreek, Mary Jeanne
中科院分区：
文献类型：
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作者：
Levran, Orna;O'Hara, Kimberly;Kreek, Mary Jeanne
美沙酮是一种多阿片受体激动剂，用于治疗阿片依赖。美沙酮的有效剂量范围很广。个体间药效差异很大的部分原因可能是遗传因素。美沙酮是转运蛋白p -糖蛋白（P-gp） 170的底物，由ABCB1 （MDR1）基因编码。因此，P-gp变异可能在美沙酮的吸收和分布中起作用。我们评估了98例美沙酮维持患者ABCB1多态性与美沙酮剂量需求之间的关系。稳定的美沙酮剂量呈正态分布，平均和中位剂量为160 mg/天（范围30-280 mg/天）。统计分析显示，基因型频率“高”（150 mg/天）和“低”（T (rs1128503)）之间存在显著差异（实验P = 0.0325）。此外，携带3位点基因型TT-TT-TT （rs1045642、rs2032582和rs1128503）的个体需要“较高”美沙酮剂量的几率约为5倍，而这三个snp杂合的个体在“较低”美沙酮剂量下稳定的几率约为3倍（点向p值= 0.026）。这些数据表明，特定的ABCB1变异可能通过影响该人群预防戒断症状和复发所需的美沙酮剂量而具有临床相关性。
Methadone is a mu-opioid receptor agonist used for treating opiate dependence. The range of effective methadone doses is broad. Part of the large inter-individual variability in efficacy may be accounted for by genetic factors. Methadone is a substrate of the transporter P-glycoprotein (P-gp) 170 that is encoded by the ABCB1 (MDR1) gene. Thus, P-gp variants may play a role in methadone absorption and distribution. We assessed the association between ABCB1 polymorphisms and methadone dose requirements in 98 methadone-maintained patients. The stabilizing methadone doses were normally distributed with a mean and median dose of 160 mg/day (range 30-280 mg/day). Statistical analysis showed significant difference in genotype frequencies between the 'higher' (> 150 mg/day) and 'lower' ( T (rs1128503) (experiment-wise P = 0.0325). Furthermore, individuals bearing the 3-locus genotype pattern TT-TT-TT (rs1045642, rs2032582 and rs1128503) have an approximately 5-fold chance of requiring the 'higher' methadone dose, while individuals heterozygous for these three SNPs have an approximately 3-fold chance of stabilizing at the 'lower' methadone dose (point-wise P-value = 0.026). These data suggest that specific ABCB1 variants may have clinical relevance by influencing the methadone dose required to prevent withdrawal symptoms and relapse in this population.