Genetic polymorphisms and their association with methotrexate polyglutamates during maintenance treatment in Korean children and young adults with acute lymphoblastic leukemia

IF 4.3 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences Pub Date : 2024-08-17 DOI:10.1016/j.ejps.2024.106878

Rihwa Choi , Min‐Ji Kim , Hee Young Ju , Ji Won Lee , Soo-Youn Lee

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引用次数: 0

Abstract

The aim of this study was to investigate the impact of genetic polymorphisms on methotrexate (MTX) metabolism in Korean children and young adults with acute lymphoblastic leukemia, specifically focusing on MTX polyglutamates (MTX-PGs) in erythrocytes, which have been rarely studied. Korean children and young adult patients undergoing maintenance therapy for acute lymphoblastic leukemia, who were receiving weekly oral MTX doses of 20 mg/m²/week, were prospectively included. We investigated erythrocyte MTX-PG (PG1 to PG5) levels, MTX-PG/MTX dose ratios, and 222 genetic polymorphisms spanning 78 genes and three intergenic areas related to MTX transport, folate cycle metabolism, purine/pyrimidine pathways, and non-pathway genes (including TPMT and NUDT15 genotypes) to explore their association with MTX metabolism. MTX-PG levels were associated with MTX dose (p < 0.05), and MTX-PG3 comprised the majority of the total MTX-PGs, with a median of 39.3 %. Various polymorphisms within the same gene demonstrated differing associations with each type of MTX-PG, underscoring the complexity of MTX pharmacogenetics. Among the polymorphisms examined, 14 across 13 genes showed significant associations with MTX-PG2–5 levels, even after adjusting for the false discovery rate (ABCC5, ATG16L1, CEP72, FSTL5, GMPS, HTR3A, IMPDH1, NT5C2, SLC28A3, SLCO1B3, SUCLA2, TPMT, and TYMS). This study enhances our understanding of genetic polymorphisms in MTX metabolism and therapeutic monitoring for MTX maintenance, promoting personalized medicine in acute lymphoblastic leukemia patients.

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韩国儿童和年轻成人急性淋巴细胞白血病患者在维持治疗期间的基因多态性及其与甲氨蝶呤多聚酶的关系。

本研究旨在调查韩国儿童和年轻成人急性淋巴细胞白血病患者的基因多态性对甲氨蝶呤（MTX）代谢的影响，特别关注红细胞中的MTX多聚谷氨酸（MTX-PGs），因为对这一问题的研究很少。前瞻性地纳入了正在接受急性淋巴细胞白血病维持治疗的韩国儿童和年轻成人患者，他们每周口服 20 毫克/平方米剂量的 MTX。我们调查了红细胞中的 MTX-PG（PG1 至 PG5）水平、MTX-PG/MTX 剂量比，以及横跨 78 个基因和 3 个基因间区域的 222 个基因多态性，这些基因涉及 MTX 转运、叶酸循环代谢、嘌呤/嘧啶通路和非通路基因（包括 TPMT 和 NUDT15 基因型），以探讨它们与 MTX 代谢的关系。MTX-PG水平与MTX剂量有关（P＜0.05），MTX-PG3占MTX-PG总数的大部分，中位数为39.3%。同一基因中的不同多态性与每种类型的 MTX-PG 都有不同的关联，这凸显了 MTX 药物遗传学的复杂性。在所研究的多态性中，13 个基因中的 14 个与 MTX-PG2-5 水平有显著关联，即使在调整了假发现率之后也是如此（ABCC5、ATG16L1、CEP72、FSTL5、GMPS、HTR3A、IMPDH1、NT5C2、SLC28A3、SLCO1B3、SUCLA2、TPMT 和 TYMS）。这项研究加深了我们对 MTX 代谢基因多态性和 MTX 维持治疗监测的了解，促进了急性淋巴细胞白血病患者的个性化医疗。

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来源期刊

European Journal of Pharmaceutical Sciences 医学-药学

CiteScore

9.60

自引率

2.20%

发文量

248

审稿时长

50 days

期刊介绍： The journal publishes research articles, review articles and scientific commentaries on all aspects of the pharmaceutical sciences with emphasis on conceptual novelty and scientific quality. The Editors welcome articles in this multidisciplinary field, with a focus on topics relevant for drug discovery and development. More specifically, the Journal publishes reports on medicinal chemistry, pharmacology, drug absorption and metabolism, pharmacokinetics and pharmacodynamics, pharmaceutical and biomedical analysis, drug delivery (including gene delivery), drug targeting, pharmaceutical technology, pharmaceutical biotechnology and clinical drug evaluation. The journal will typically not give priority to manuscripts focusing primarily on organic synthesis, natural products, adaptation of analytical approaches, or discussions pertaining to drug policy making. Scientific commentaries and review articles are generally by invitation only or by consent of the Editors. Proceedings of scientific meetings may be published as special issues or supplements to the Journal.