Comparative study on the pharmacokinetics of 7-hydroxy-methotrexate after administration of methotrexate in the dose range of 0.5-33.6 g/m2 to children with acute lymphoblastic leukemia.
Concentrations of 7-hydroxy-methotrexate (7-OH-MTX) were determined in serum samples obtained after 266 infusions of methotrexate administered to 58 children with acute lymphoblastic leukemia. The dose of methotrexate (MTX) was in the range of 0.5-33.6 g/m2. Pharmacokinetic parameters (metabolic index, drug/metabolite ratio, half-life) of 7-OH-MTX and their relationship to the kinetics of methotrexate were analyzed. A great variability was observed in the extent and time-course of the metabolite formation. The concentration of the metabolite was higher than that of the parent compound at any examined time after the end of the 24 hours' infusion. The increase of 7-OH-MTX levels at the end of the methotrexate infusion was found to be proportionate to the increase of the dose of MTX. Males had significantly higher metabolite levels than did females (P less than 0.01) in the dose range of 0.5-8.0 g/m2. The age of the patients also significantly influenced the rate of the metabolite formation. The serial number of the treatment courses did not have effect on the metabolism of MTX. Dose dependency of the elimination half-life of the metabolite was found. Although a tendency was observed that patients in continuous complete remission had higher metabolite levels than those who relapsed, the difference was not significant. Further studies are needed to determine the clinical importance of 7-OH-MT.
Borsi
J D
JD
Department of Paediatrics, University of Trondheim, Norway.
Sagen
E
E
Romslo
I
I
Moe
P J
PJ
D000293:Adolescent; D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006801:Humans; D007223:Infant; D007700:Kinetics; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D012074:Remission Induction; D012737:Sex Factors
C011864:7-hydroxymethotrexate; D008727:Methotrexate