Methadone Pharmacogenetics: CYP2B6 Polymorphisms Determine Plasma Concentrations, Clearance, and Metabolism.
Methadone Pharmacogenetics: CYP2B6 Polymorphisms Determine Plasma Concentrations, Clearance, and Metabolism.
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DOI：
10.1097/aln.0000000000000867
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发表时间：
2015-11
期刊：
影响因子：
8.8
通讯作者：
Friedel C
中科院分区：
文献类型：
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作者：
Kharasch ED;Regina KJ;Blood J;Friedel C
美沙酮处置的个体间差异仍然无法解释，美沙酮意外过量的疼痛治疗是一个重要的公共卫生问题。细胞色素P4502 B6（CYP 2B 6）是美沙酮临床消除的主要决定因素。CYP 2B 6基因具有高度多态性，有几个变异等位基因。CYP2B6.6是由CYP 2B 6 *6多态性编码的蛋白质，在体外催化美沙酮代谢不足。本研究确定了CYP 2B 6 *6和遇到的其他等位基因变体对美沙酮浓度、清除率和代谢的影响。基因型队列CYP 2B 6 *1/*1（n=21）、CYP 2B 6 *1/*6（n=20）和CYP 2B 6 *6/*6（n=17）中的健康志愿者，以及CYP 2B 6 *1/*4（n=1）、CYP 2B 6 *4/*6（n=3）、CYP 2B 6 *5/*5（n=2）受试者接受单次静脉和口服美沙酮给药。血浆和尿液中美沙酮和代谢物的浓度通过串联质谱法测定。与CYP 2B 6 *1/*1相比，CYP 2B 6 *1/*6和CYP 2B 6 *6/*6基因型的平均S-美沙酮表观口服清除率分别低35%和45%，R-美沙酮表观口服清除率低25%和30%。在CYP 2B 6 *4携带者中，R-和S-美沙酮表观口服清除率分别高3倍和4倍。静脉和口服R-和S-美沙酮代谢在CYP 2B 6 *6携带者中显著低于CYP 2B 6 *1纯合子，而在CYP 2B 6 *4携带者中更高。由于CYP 2B 6 *6基因多态性，非裔美国人的美沙酮代谢和清除率较低。CYP 2B 6多态性影响美沙酮血浆浓度，这是由于美沙酮代谢改变，从而清除。口服美沙酮的遗传影响大于静脉注射，S-美沙酮的遗传影响大于R-美沙酮。CYP 2B 6药物遗传学部分解释了美沙酮消除的个体间差异。CYP 2B 6对美沙酮代谢和清除的遗传效应可识别美沙酮毒性和药物相互作用风险的受试者。
Interindividual variability in methadone disposition remains unexplained, and methadone accidental overdose in pain therapy is a significant public health problem. Cytochrome P4502B6 (CYP2B6) is the principle determinant of clinical methadone elimination. The CYP2B6 gene is highly polymorphic, with several variant alleles. CYP2B6.6, the protein encoded by the CYP2B6*6 polymorphism, deficiently catalyzes methadone metabolism in vitro. This investigation determined the influence of CYP2B6*6, and other allelic variants encountered, on methadone concentrations, clearance, and metabolism. Healthy volunteers in genotype cohorts CYP2B6*1/*1 (n=21), CYP2B6*1/*6 (n=20), and CYP2B6*6/*6 (n=17), and also CYP2B6*1/*4 (n=1), CYP2B6*4/*6 (n=3), CYP2B6*5/*5 (n=2) subjects received single doses of intravenous and oral methadone. Plasma and urine methadone and metabolite concentrations were determined by tandem mass spectrometry. Average S-methadone apparent oral clearance was 35 and 45% lower in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively, compared with CYP2B6*1/*1, and R-methadone apparent oral clearance was 25 and 30% lower. R- and S-methadone apparent oral clearance was 3- and 4-fold greater in CYP2B6*4 carriers. Intravenous and oral R- and S-methadone metabolism was significantly lower in CYP2B6*6 carriers compared with CYP2B6*1 homozygotes, and greater in CYP2B6*4 carriers. Methadone metabolism and clearance were lower in African-Americans due to the CYP2B6*6 genetic polymorphism. CYP2B6 polymorphisms influence methadone plasma concentrations, due to altered methadone metabolism and thus clearance. Genetic influence is greater for oral than intravenous, and S- than R-methadone. CYP2B6 pharmacogenetics explains, in part, interindividual variability in methadone elimination. CYP2B6 genetic effects on methadone metabolism and clearance may identify subjects at risk for methadone toxicity and drug interactions.