ABCB1和CYP2B6基因多态性对阿片类药物成瘾患者美沙酮代谢、剂量及治疗反应的影响：一项系统评价和荟萃分析
Impact of ABCB1 and CYP2B6 genetic polymorphisms on methadone metabolism, dose and treatment response in patients with opioid addiction: a systematic review and meta-analysis.
作者信息
Dennis Brittany B, Bawor Monica, Thabane Lehana, Sohani Zahra, Samaan Zainab
机构信息
Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada ; Biostatistics Unit, Father Sean O'Sullivan Research Centre, St Joseph's Healthcare, Hamilton, Ontario, Canada ; Population Genomics Program, McMaster University, Hamilton, Ontario, Canada.
Population Genomics Program, McMaster University, Hamilton, Ontario, Canada ; McMaster Integrative Neuroscience Discovery & Study (MiNDS) Program, McMaster University, Hamilton, Ontario, Canada.
出版信息
PLoS One. 2014 Jan 29;9(1):e86114. doi: 10.1371/journal.pone.0086114. eCollection 2014.
BACKGROUND
Genetic variability may influence methadone metabolism, dose requirements, and risk of relapse.
OBJECTIVES
To determine whether the CYP2B6*6 or ABCB1 (rs1045642) polymorphisms are associated with variation in methadone response (plasma concentration, dose, or response to treatment).
METHODS
Two independent reviewers searched Medline, EMBASE, CINAHL, PsycINFO, and Web of Science databases. We included studies that reported methadone plasma concentration, methadone response, or methadone dose in relation to the CYP2B6*6 or ABCB1 polymorphisms.
RESULTS
We screened 182 articles and extracted 7 articles for inclusion in the meta-analysis. Considerable agreement was observed between the two independent raters on the title (kappa, 0.82), abstract (kappa, 0.43), and full text screening (kappa, 0.43). Trough (R) methadone plasma concentration was significantly higher in CYP2B6*6 homozygous carriers when compared to non-carriers (standardized mean difference [SMD] = 0.53, 95% confidence interval [CI], 0.05-1.00, p = 0.03) with minimal heterogeneity (I(2) = 0%). Similarly, trough (S) methadone plasma concentration was higher in homozygous carriers of the 6 haplotype when compared to non-carriers, (SMD = 1.44, 95% CI 0.27-2.61, p = 0.02) however significant heterogeneity was observed (I(2) = 69%). Carriers of the CYP2B66 haplotype were not found to be significantly different from non-carriers with respect to dose or response to treatment. We found no significant association between the ABCB1 polymorphism and the trough (R), (S) plasma concentrations, methadone dose, or methadone response.
CONCLUSION
Although the number of studies included and sample size were modest, this is the first meta analysis to show participants homozygous for the CYP2B6*6 genotype have higher trough (R) and (S) methadone plasma concentrations, suggesting that methadone metabolism is significantly slower in *6 homozygous carriers.
背景
基因变异性可能影响美沙酮代谢、剂量需求及复发风险。
目的
确定细胞色素P450 2B6（CYP2B6）*6或ATP结合盒转运蛋白B1（ABCB1，rs1045642）基因多态性是否与美沙酮反应（血浆浓度、剂量或治疗反应）的差异相关。
方法
两名独立评审员检索了医学文献数据库（Medline）、荷兰医学文摘数据库（EMBASE）、护理学与健康领域数据库（CINAHL）、心理学文摘数据库（PsycINFO）及科学引文索引数据库（Web of Science）。我们纳入了报告美沙酮血浆浓度、美沙酮反应或美沙酮剂量与CYP2B6*6或ABCB1基因多态性之间关系的研究。
结果
我们筛选了182篇文章，并提取了7篇文章纳入荟萃分析。两位独立评分者在标题（卡方值，0.82）、摘要（卡方值，0.43）和全文筛选（卡方值，0.43）方面观察到相当高的一致性。与非携带者相比，CYP2B6*6纯合子携带者的美沙酮血浆谷浓度显著更高（标准化均数差[SMD]=0.53，95%置信区间[CI]，0.05 - 1.00，p = 0.03），异质性最小（I² = 0%）。同样，与非携带者相比，6单倍型纯合子携带者的美沙酮血浆谷浓度更高（SMD = 1.44，95% CI 0.27 - 2.61，p = 0.02），但观察到显著的异质性（I² = 69%）。未发现CYP2B66单倍型携带者与非携带者在剂量或治疗反应方面存在显著差异。我们发现ABCB1基因多态性与美沙酮血浆谷浓度（R）、（S）、美沙酮剂量或美沙酮反应之间无显著关联。
结论
尽管纳入的研究数量和样本量不大，但这是第一项荟萃分析表明，CYP2B66基因型纯合子参与者的美沙酮血浆谷浓度（R）和（S）更高，这表明6纯合子携带者的美沙酮代谢明显较慢。
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