Eum Seenae, Vernacchia Nicholas P, Doughty Nia, Mehrzad Sahar, Talal Andrew H, Chalabianloo Fatemeh, Kharasch Evan D
Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA.
Department of Pharmacogenomics, School of Pharmacy, Shenandoah University, Fairfax, VA, USA.
Expert Opin Drug Metab Toxicol. 2024 Nov 28:1-16. doi: 10.1080/17425255.2024.2432664.
Confusion regarding methadone metabolism exists, hampering optimal clinical use. A systematic review was conducted to assess the impacts of cytochrome P450 (CYP) genetic polymorphisms on methadone outcomes.
MEDLINE, EMBASE, Web of Science, PsycINFO, and CENTRAL were searched to identify studies reporting methadone dose-adjusted plasma concentrations, clearance, maintenance dose, or treatment response in relation to polymorphisms in humans. ROBINS-I was used to evaluate risk of bias in included studies. Each outcome was synthesized for each CYP using the ratio of means or odds ratio as the effect size measure.
Ten, two, fourteen, and five studies were included in the meta-analyses of the concentration, clearance, dose, and treatment response, respectively. The c.516 G>T variant was robustly associated with (S)-methadone concentrations (GT+TTvs.GG: ratio of means (RoM) 1.40, < 0.01) and clearance (GT+TTvs.GG: RoM 0.65, < 0.01) but less with (R)- or (R,S)-methadone. The variant also affected methadone dose for opioid use disorder (GT+TTvs.GG: RoM 0.93, = 0.04). , , , and polymorphisms did not influence any of the assessed outcomes.
CYP2B6 genetics had statistically significant impacts on (S)-methadone and less so on (R)-methadone exposure and clearance and was statistically significantly but not clinically meaningfully associated with dose requirements.
关于美沙酮代谢存在混淆，这妨碍了其最佳临床应用。本研究进行了一项系统评价，以评估细胞色素P450（CYP）基因多态性对美沙酮治疗效果的影响。
检索了MEDLINE、EMBASE、科学引文索引、心理学文摘数据库和考克兰系统评价数据库，以确定报告美沙酮剂量调整后的血浆浓度、清除率、维持剂量或治疗反应与人类基因多态性之间关系的研究。采用ROBINS-I评估纳入研究的偏倚风险。使用均值比或优势比作为效应量指标，对每种CYP的各项结局进行综合分析。
分别有10项、2项、14项和5项研究纳入了浓度、清除率、剂量和治疗反应的荟萃分析。c.516 G>T变异与（S）-美沙酮浓度（GT+TT与GG：均值比（RoM）1.40，<0.01）和清除率（GT+TT与GG：RoM 0.65，<0.01）密切相关，但与（R）-或（R,S）-美沙酮的相关性较弱。该变异也影响阿片类物质使用障碍的美沙酮剂量（GT+TT与GG：RoM 0.93，=0.04）。CYP2C8、CYP2C9、CYP2D6和CYP3A4基因多态性未影响任何评估结局。
CYP2B6基因对（S）-美沙酮有统计学显著影响，对（R）-美沙酮暴露和清除率的影响较小，且与剂量需求存在统计学显著但无临床意义的关联。
