Renal excretion and pharmacokinetics of methotrexate and 7-hydroxy-methotrexate following a 24-h high dose infusion of methotrexate in children.
In children with lymphoid malignancies 18 courses of methotrexate (18-200 mg/kg) administered as a 24-h infusion were monitored. Plasma concentrations and renal excretion rates of methotrexate (MTX) and 7-hydroxymethotrexate (7-OHMTX) were determined. A low correlation was found between the administered dose of MTX and the body exposure to MTX or 7-OHMTX. Although 84% of the MTX eventually recovered from the urine was excreted during the 24 h of the infusion, the renal clearance of MTX was markedly lower during the time of the infusion than after it. There were courses with a low and others with a high renal clearance of MTX during the infusion, despite the same urine flow. A low MTX renal clearance was correlated with a high body exposure to MTX. As the same variations were also seen in the same patient during successive courses, pharmacokinetical characterization of patients appears questionable. The renal clearance of 7-OHMTX was significantly lower than the renal clearance of MTX, and the body exposure to 7-OHMTX ranged from 2-40% of the MTX body exposure. Treatment courses with a low or a high body exposure to 7-OHMTX were not associated with different urinary recoveries of the metabolite. Differences in MTX hydroxylation could not be substantiated. Because the concentration of 7-OHMTX is high soon after the end of an infusion, a specific method of MTX determination should be chosen for controlling treatment.
Winograd
B
B
Lippens
R J
RJ
Oosterbaan
M J
MJ
Dirks
M J
MJ
Vree
T B
TB
van der Kleijn
E
E
D002648:Child; D005260:Female; D006801:Humans; D007263:Infusions, Parenteral; D007677:Kidney Function Tests; D007700:Kinetics; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000652:urine*
C011864:7-hydroxymethotrexate; D008727:Methotrexate