Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyotanabe, 610-0395, Japan; Division of Medical Safety Science, National Institute of Health Sciences, Kawasaki, 210-9501, Japan.
Department of Clinical Oncology, Kawasaki Medical School, Kurashiki, 701-0192, Japan.
Drug Metab Pharmacokinet. 2022 Apr;43:100441. doi: 10.1016/j.dmpk.2021.100441. Epub 2021 Dec 22.
Although imatinib has dramatically improved the outcomes of patients with gastrointestinal stromal tumor (GIST), marked inter-individual differences in its efficacy and toxicity have been observed. Extensive pharmacogenetic studies in Caucasian and Asian populations have demonstrated that several genetic polymorphisms are involved in these differences; however, no studies have focused on Japanese patients with GIST. This study aimed to evaluate the impacts of genetic polymorphisms of drug metabolizing enzymes and transporters on the incidence of adverse events and trough plasma concentrations (Cs) of imatinib in Japanese patients with GIST. Of 35 candidate SNPs genotyped from 65 patients, ABCG2 421C>A was significantly associated with increased incidence rates of grade 2 or higher rash. When relationships between the genotypes and Cs were examined in a subgroup of 38 patients from whom plasma was available, 5 SNPs were associated with significant trends toward increased or decreased dose-adjusted Cs. Of them, SLCO1B3 334T>G and SLCO1A2 -1032G>A made significant contributions to the individual variability of C by multivariate regression analysis. Genetic variations in ABCG2, SLCO1B3, and SLCO1A2 may play important roles in the safety and pharmacokinetics of imatinib in Japanese patients with GIST, although a replication study is necessary for validation.
虽然伊马替尼显著改善了胃肠道间质瘤（GIST）患者的预后，但在其疗效和毒性方面存在显著的个体间差异。在白人和亚洲人群中的广泛药物遗传学研究表明，几种遗传多态性与这些差异有关；然而，尚无研究关注日本 GIST 患者。本研究旨在评估药物代谢酶和转运体的遗传多态性对日本 GIST 患者不良事件发生率和伊马替尼谷浓度（Cs）的影响。在 65 例患者中对 35 个候选 SNP 进行基因分型，ABCG2 421C>A 与 2 级或更高级皮疹的发生率增加显著相关。在可获得血浆的 38 例患者亚组中检查基因型与 Cs 的关系时，有 5 个 SNP 与 Cs 的剂量调整呈显著趋势相关。其中，SLCO1B3 334T>G 和 SLCO1A2-1032G>A 对多元回归分析的 C 个体变异性有显著贡献。ABCG2、SLCO1B3 和 SLCO1A2 的遗传变异可能在日本 GIST 患者中伊马替尼的安全性和药代动力学中发挥重要作用，尽管需要进行复制研究来验证。
