Methotrexate polyglutamate quantification for clinical application in patients with pediatric acute lymphoblastic leukemia in association with genetic polymorphisms.

Autor: Choi R; Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Department of Laboratory Medicine, Green Cross Laboratories, Yongin, Gyeonggi, Republic of Korea., Chun MR; Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea., Park J; Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea., Won H; Statistics and Data Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea., Kim S; Statistics and Data Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea., Lee JW; Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address: leejw.lee@samsung.com., Ju HY; Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea., Cho HW; Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea., Hyun JK; Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea., Koo HH; Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea., Yi ES; Department of Pediatrics, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea., Lee SY; Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Department of Health Science and Technology, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea. Electronic address: suddenbz@skku.edu.
Jazyk: angličtina
Zdroj: Journal of pharmaceutical and biomedical analysis [J Pharm Biomed Anal] 2021 Jul 15; Vol. 201, pp. 114124. Date of Electronic Publication: 2021 May 05.
DOI: 10.1016/j.jpba.2021.114124
Abstrakt: 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.
Competing Interests: Declaration of Competing Interest The authors report no declarations of interest.
(Copyright © 2021. Published by Elsevier B.V.)
Databáze: MEDLINE
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