Methotrexate polyglutamate quantification for clinical application in patients with pediatric acute lymphoblastic leukemia in association with genetic polymorphisms
- Authors
- Choi, Rihwa; Chun, Mi Ryung; Park, Jisook; Won, Hojeong; Kim, Seonwoo; Lee, Ji Won; Ju, Hee Young; Cho, Hee Won; Hyun, Ju Kyung; Koo, Hong Hoe; Yi, Eun Sang; Lee, Soo Youn
- Issue Date
- 15-Jul-2021
- Publisher
- Elsevier B.V.
- Keywords
- Acute lymphoblastic leukemia; Methotrexate; Methotrexate polyglutamates; Tandem mass spectrometry; Therapeutic drug monitoring
- Citation
- Journal of Pharmaceutical and Biomedical Analysis, v.201
- Indexed
- SCIE
SCOPUS
- Journal Title
- Journal of Pharmaceutical and Biomedical Analysis
- Volume
- 201
- URI
- https://scholarworks.korea.ac.kr/kumedicine/handle/2020.sw.kumedicine/53870
- DOI
- 10.1016/j.jpba.2021.114124
- ISSN
- 0731-7085
1873-264X
- Abstract
- We developed and validated a quantification method for methotrexate (MTX) polyglutamates (MTX-PGs, MTX-PG1 to MTX-PG5) by liquid chromatography-tandem mass spectrometry using stable isotope-labeled internal standards and applied to 196 clinical samples collected from pediatric acute lymphoblastic leukemia patients treated with MTX. MTX-PGs levels and their proportions (%) in sum of all MTX-PGs (MTXSum) were evaluated in relation to TPMT, NUDT15, and MTHFR genotypes. For the developed method, linearity ranges 1−500 nmol/L, bias for accuracy 0.3–13.5 %, coefficient of variation for within- and between-run imprecision of 3.2−9.5% and 1.5−12.0%, respectively. Recoveries achieved were 74.2–105.8 %. There was no significant carryover. The median level of the MTXSum for 196 clinical samples was 129.4 nmol/L (interquartile range 28.1−241.2). MTX dose and MTX-PGs were associated (P < 0.05) and among five MTX-PGs, MTX-PG3 was the predominant form (median 41.7 %). The MTX-PG3 level was significantly higher in patients with TPMT *1/*3C than in patients with wild type and MTX-PG3% was significantly higher and MTX-PG5% was significantly lower in NUDT15 intermediate metabolizers than normal or indeterminate phenotypes (P < 0.05). This validated MTX-PGs quantification method can facilitate a better understanding of MTX metabolism and therapeutic drug monitoring for MTX treatment. © 2021
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Collections - 2. Clinical Science > Department of Pediatrics > 1. Journal Articles
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