Influence of pre-hydration and pharmacogenetics on plasma methotrexate concentration and renal dysfunction following high-dose methotrexate therapy.
High-dose methotrexate therapy (HD-MTX) has been well established for the treatment of childhood acute lymphoblastic leukemia (ALL). The aims of this study were to investigate whether clinical and pharmacogenetic factors influence plasma MTX concentration and renal dysfunction in patients treated with HD-MTX. In a total of 127 courses of HD-MTX in 51 patients with childhood ALL, influence of clinical and pharmacogenetic factors on plasma MTX concentration and HD-MTX-related renal dysfunction was evaluated. Clinical factors included age, gender, duration of HD-MTX continuous-infusion and duration of pre-hydration before HD-MTX. Pharmacogenetic factors included 5 gene polymorphisms within the MTX pathway genes, namely, SLC19A1, MTHFR, ABCC2 and ABCG2. Short duration of pre-hydration before HD-MTX is the most important risk factor for prolonged high MTX concentration (p < 0.001, OR 6.40, 95 % CI 2.39-17.16) and renal dysfunction (p = 0.013, OR 3.15, 95 % CI 1.27-7.80). The T allele at MTHFR C677T was the risk factor for prolonged high MTX concentration (p = 0.009, OR 5.54, 95 % CI 1.54-19.85), but not for renal dysfunction. We found the influence of MTHFR C677T polymorphism on prolonged high MTX concentration. We reconfirmed the importance of adequate pre-hydration before HD-MTX to prevent prolonged high MTX concentration and MTX-related renal dysfunction.
Department of Pediatrics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan, myanagi@yokohama-cu.ac.jp.
Masakatsu
M
Yanagimachi
Hiroaki
H
Goto
Tetsuji
T
Kaneko
Takuya
T
Naruto
Koji
K
Sasaki
Masanobu
M
Takeuchi
Reo
R
Tanoshima
Hiromi
H
Kato
Tomoko
T
Yokosuka
Ryosuke
R
Kajiwara
Hisaki
H
Fujii
Fumiko
F
Tanaka
Shoko
S
Goto
Hiroyuki
H
Takahashi
Masaaki
M
Mori
Sumio
S
Kai
Shumpei
S
Yokota
D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D000089762:Multidrug Resistance-Associated Protein 2; D016017:Odds Ratio; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy; D012189:Retrospective Studies
C000715087:ABCC2 protein, human; D000964:Antimetabolites, Antineoplastic; D000089762:Multidrug Resistance-Associated Protein 2; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008727:Methotrexate