Clinical Pharmacology Department, Hospital Universitario de La Princesa, Faculty of Medicine, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria La Princesa (IP), Madrid, Spain.
Anesthesia and Surgical Critical Care Department, Hospital Universitario de la Princesa, Madrid, Spain.
Clin Transl Sci. 2024 Jan;17(1):e13698. doi: 10.1111/cts.13698.
Tramadol is an important minor opioid prescribed for pain management. In this study, we analyzed the well-known impact of CYP2D6 genetic variation and 60 additional variants in eight candidate genes (i.e., ABCG2, SLCO1B1, CYP2D6, CYP2B6, CYP2C19, CYP2C9, CYP3A5, and CYP3A4) on tramadol efficacy and safety. Some 108 patients with pain after surgery admitted to a post-anesthesia care unit (PACU) and prescribed tramadol were recruited. They were genotyped, and tramadol M1/M2 metabolite concentrations were determined by a newly validated HPLC-MS/MS method. CYP2D6 intermediate (IM) and poor (PM) metabolizers showed lower M1 concentrations adjusted for dose/weight at 30 and 120 min compared to ultrarapid (UM) and normal (NM) metabolizers (univariate p < 0.001 and 0.020, multivariate p < 0.001 and 0.001, unstandardized β coefficients = 0.386 and 0.346, R = 0.146 and 0.120, respectively). CYP2B6 PMs (n = 10) were significantly related to a higher reduction in pain 30 min after tramadol intake (univariate p = 0.038, multivariate p = 0.016, unstandardized β coefficient = 0.224, R = 0.178), to lower PACU admission time (p = 0.007), and to lower incidence of adverse drug reactions (p = 0.038) compared to the other phenotypes. CYP3A4 IMs and PMs showed a higher prevalence of drowsiness and dizziness (p = 0.028 and 0.005, respectively). Our results suggest that the interaction of CYP2B6 and CYP2D6 phenotypes may be clinically relevant, pending validation of these results in large, independent cohorts. Additional research is required to clarify the impact of CYP3A4 genetic variation on tramadol response.
曲马多是一种重要的弱阿片类药物，用于疼痛管理。在这项研究中，我们分析了 CYP2D6 遗传变异和八个候选基因（即 ABCG2、SLCO1B1、CYP2D6、CYP2B6、CYP2C19、CYP2C9、CYP3A5 和 CYP3A4）中 60 个额外变异对曲马多疗效和安全性的已知影响。我们招募了 108 名手术后入住麻醉后护理病房（PACU）并接受曲马多治疗的疼痛患者。对他们进行基因分型，并使用新验证的 HPLC-MS/MS 方法测定曲马多 M1/M2 代谢物浓度。与超快代谢（UM）和正常代谢（NM）相比，CYP2D6 中间代谢（IM）和弱代谢（PM）代谢物的 30 分钟和 120 分钟时的剂量/体重调整后的 M1 浓度较低（单变量 p < 0.001 和 0.020，多变量 p < 0.001 和 0.001，未标准化的β系数= 0.386 和 0.346，R 2 = 0.146 和 0.120）。CYP2B6 PM （n = 10）与曲马多摄入后 30 分钟疼痛减轻（单变量 p = 0.038，多变量 p = 0.016，未标准化的β系数= 0.224，R 2 = 0.178）、PACU 入院时间缩短（p = 0.007）和不良反应发生率降低（p = 0.038）显著相关。与其他表型相比，CYP3A4 IM 和 PM 出现嗜睡和头晕的比例更高（p = 0.028 和 0.005）。我们的结果表明，CYP2B6 和 CYP2D6 表型的相互作用可能具有临床意义，有待在大型独立队列中验证这些结果。需要进一步研究以阐明 CYP3A4 遗传变异对曲马多反应的影响。
