de Moraes Natália V, Lauretti Gabriela R, Coelho Eduardo B, Godoy Ana Leonor P C, Neves Daniel V, Lanchote Vera L
Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, ZIP 14801-902, Araraquara, SP, Brazil.
Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, ZIP 14049-900, Ribeirão Preto, SP, Brazil.
Fundam Clin Pharmacol. 2016 Apr;30(2):153-61. doi: 10.1111/fcp.12168. Epub 2015 Dec 11.
The pharmacokinetics of tramadol is characterized by a large interindividual variability, which is partially attributed to polymorphic CYP2D6 metabolism. The contribution of CYP3A, CYP2B6, fraction unbound, and other potential covariates remains unknown. This study aimed to investigate the contribution of in vivo activities of cytochrome P450 (CYP) 2D6 and 3A as well as other potential covariates (CYP2B6 genotype to the SNP g.15631G>T, fraction unbound, age, body weight, creatinine clearance) to the enantioselective pharmacokinetics of tramadol. Thirty patients with neuropathic pain and phenotyped as CYP2D6 extensive metabolizers were treated with a single oral dose of 100 mg tramadol. Multiple linear regressions were performed to determine the contribution of CYP activities and other potential covariates to the clearance of tramadol enantiomers. The apparent total clearances were 44.9 (19.1-102-2) L/h and 55.2 (14.8-126.0) L/h for (+)- and (-)-tramadol, respectively [data presented as median (minimum-maximum)]. Between 79 and 83% of the overall variation in apparent clearance of tramadol enantiomers was explained by fraction unbound, CYP2D6, and CYP3A in vivo activities and body weight. Fraction unbound explained 47 and 41% of the variation in clearance of (+)-tramadol and (-)-tramadol, respectively. Individually, CYP2D6 and CYP3A activities were shown to have moderate contribution on clearance of tramadol enantiomers (11-16% and 11-18%, respectively). In conclusion, factors affecting fraction unbound of drugs (such as hyperglycemia or co-administration of drugs highly bound to plasma proteins) should be monitored, because this parameter dominates the elimination of tramadol enantiomers.
曲马多的药代动力学特征是个体间差异很大，部分原因是CYP2D6代谢存在多态性。CYP3A、CYP2B6、未结合分数以及其他潜在协变量的作用尚不清楚。本研究旨在调查细胞色素P450（CYP）2D6和3A的体内活性以及其他潜在协变量（CYP2B6基因的g.15631G>T单核苷酸多态性、未结合分数、年龄、体重、肌酐清除率）对曲马多对映体选择性药代动力学的影响。30例患有神经性疼痛且表型为CYP2D6广泛代谢型的患者口服100 mg曲马多单剂量。进行多元线性回归以确定CYP活性和其他潜在协变量对曲马多对映体清除率的影响。（+）-和（-）-曲马多的表观总清除率分别为44.9（19.1-102.2）L/h和55.2（14.8-126.0）L/h [数据以中位数（最小值-最大值）表示]。曲马多对映体表观清除率总体变化的79%至83%可由未结合分数、CYP2D6和CYP3A的体内活性以及体重来解释。未结合分数分别解释了（+）-曲马多和（-）-曲马多清除率变化的47%和41%。单独来看，CYP2D6和CYP3A活性对曲马多对映体清除率有中等贡献（分别为11%-16%和11%-18%）。总之，应监测影响药物未结合分数的因素（如高血糖或与血浆蛋白高度结合的药物共同给药），因为该参数主导着曲马多对映体的消除。
