Kharasch Evan D, Regina Karen J, Blood Jane, Friedel Christina
From the Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri (E.D.K., K.J.R., J.B., C.F.); and Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, St. Louis, Missouri (E.D.K.).
Anesthesiology. 2015 Nov;123(5):1142-53. doi: 10.1097/ALN.0000000000000867.
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 CYP2B66 polymorphism, deficiently catalyzes methadone metabolism in vitro. This investigation determined the influence of CYP2B66, and other allelic variants encountered, on methadone concentrations, clearance, and metabolism.
Healthy volunteers in genotype cohorts CYP2B6*1/1 (n = 21), CYP2B61/6 (n = 20), and CYP2B66/6 (n = 17), and also CYP2B61/4 (n = 1), CYP2B64/6 (n = 3), and CYP2B65/*5 (n = 2) subjects, received single doses of IV 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 CYP2B61/6 and CYP2B66/6 genotypes, respectively, compared with CYP2B61/1. R-methadone apparent oral clearance was 25 and 35% lower in CYP2B61/6 and CYP2B66/6 genotypes, respectively, compared with CYP2B61/1. R- and S-methadone apparent oral clearance was threefold and fourfold greater in CYP2B64 carriers. IV and oral R- and S-methadone metabolism was significantly lower in CYP2B66 carriers compared with that of CYP2B61 homozygotes and greater in CYP2B64 carriers. Methadone metabolism and clearance were lower in African Americans in part because of the CYP2B6*6 genetic polymorphism.
CYP2B6 polymorphisms influence methadone plasma concentrations, because of altered methadone metabolism and thus clearance. Genetic influence is greater for oral than IV methadone 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.
美沙酮处置的个体间差异仍无法解释，且疼痛治疗中美沙酮意外过量是一个重大的公共卫生问题。细胞色素P4502B6（CYP2B6）是临床美沙酮消除的主要决定因素。CYP2B6基因具有高度多态性，存在多个变异等位基因。CYP2B6.6是由CYP2B66多态性编码的蛋白质，在体外催化美沙酮代谢的能力不足。本研究确定了CYP2B66以及其他所遇到的等位基因变异对美沙酮浓度、清除率和代谢的影响。
基因型队列中的健康志愿者，CYP2B6*1/1（n = 21）、CYP2B61/6（n = 20）和CYP2B66/6（n = 17），还有CYP2B61/4（n = 1）、CYP2B64/6（n = 3）和CYP2B65/*5（n = 2）受试者，接受单次静脉注射和口服美沙酮。通过串联质谱法测定血浆和尿液中美沙酮及其代谢物的浓度。
与CYP2B61/1基因型相比，CYP2B61/6和CYP2B66/6基因型的S-美沙酮平均表观口服清除率分别降低35%和45%。与CYP2B61/1基因型相比，CYP2B61/
