Metropolitan Autonomous University, Campus Xochimilco, Mexico City, Mexico.
Biosanitary Research Institute of Extremadura (INUBE), University of Extremadura, Badajoz, Spain.
Pharmacogenomics J. 2020 Dec;20(6):845-856. doi: 10.1038/s41397-020-0173-2. Epub 2020 Jun 2.
Genetic and nongenetic factors may contribute to lamotrigine (LTG) plasma concentration variability among patients. We simultaneously investigated the association of UGT1A1, UGT1A4, UGT2B7, ABCB1, ABCG2, and SLC22A1 variants, as well as antiepileptic drug co-treatment, on LTG plasma concentration in 97 Mexican Mestizo (MM) patients with epilepsy. UGT1A41b was associated with lower LTG dose-corrected concentrations. Patients with the UGT2B7-161T allele were treated with 21.22% higher LTG daily dose than those with CC genotype. Two novel UGT1A4 variants (c.526A>T; p.Thr185= and c.496T>C; p.Ser166Leu) were identified in one patient. Patients treated with LTG + valproic acid (VPA) showed higher LTG plasma concentration than patients did on LTG monotherapy or LTG + inducer. Despite the numerous drug-metabolizing enzymes and transporter genetic variants analyzed, our results revealed that co-treatment with VPA was the most significant factor influencing LTG plasma concentration, followed by UGT1A41b, and that patients carrying UGT2B7 c.-161T required higher LTG daily doses. These data provide valuable information for the clinical use of LTG in MM patients with epilepsy.
遗传和非遗传因素可能导致拉莫三嗪（LTG）在患者体内的血浆浓度存在差异。我们同时研究了 UGT1A1、UGT1A4、UGT2B7、ABCB1、ABCG2 和 SLC22A1 变异，以及抗癫痫药物联合治疗，对 97 名墨西哥梅斯蒂索（MM）癫痫患者 LTG 血浆浓度的影响。UGT1A41b 与 LTG 剂量校正浓度降低有关。携带 UGT2B7-161T 等位基因的患者接受的 LTG 日剂量比 CC 基因型患者高 21.22%。在一名患者中发现了两种新的 UGT1A4 变体（c.526A>T；p.Thr185=和 c.496T>C；p.Ser166Leu）。与 LTG 单药治疗或 LTG+诱导剂相比，接受 LTG+丙戊酸（VPA）治疗的患者 LTG 血浆浓度更高。尽管分析了许多药物代谢酶和转运体的遗传变异，但我们的结果表明，与 VPA 的联合治疗是影响 LTG 血浆浓度的最重要因素，其次是 UGT1A41b，并且携带 UGT2B7 c.-161T 的患者需要更高的 LTG 日剂量。这些数据为 LTG 在 MM 癫痫患者中的临床应用提供了有价值的信息。
