European Journal of Clinical Pharmacology

, Volume 39, Issue 4, pp 377–383 | Cite as

Pharmacokinetic study of methotrexate, folinic acid and their serum metabolites in children treated with high-dose methotrexate and leucovorin rescue

  • C. Wolfrom
  • R. Hepp
  • R. Hartmann
  • H. Breithaupt
  • G. Henze


The pharmacokinetics of methotrexate (MTX), 7-hydroxymethotrexate (7-OHMTX), 2,4-diaminomethylpteroic acid (APA), folinic acid, and 5-methyltetrahydrofolate (5-MTHF) have been studied during 21 high-dose MTX (HDMTX) infusions (5 g·m−2 in 24 h) with leucovorin (LCV) rescue, a component of the therapy of 5 children with acute lymphoblastic leukemia (ALL).

The median steady-state concentration of MTX was 66 μmol·l−1. Three elimination half-lifes were determined for MTX: 1.8 h, 6.4 h and a terminal 15 h. The median systemic MTX clearance was 110 mg·m−2·min−1.

The 7-OHMTX level increased during each infusion and a Cmax of 19 μmol·l−1 was achieved at the end. Its initial half-life was 5 h and the terminal half-life was 12 h. Thus, the peak serum concentration ratio of 7-OHMTX to MTX was reached 24 h after the end of the infusion at a median ratio of 8.

The MTX metabolite APA was detected in concentrations less than 0.06 μmol·l−1. The median folinic acid level during rescue, 48 h after starting the infusion, was 7.0 μmol·l−1 and 18 h following the last dose of LCV it was 0.44 μmol·l−1, leading to ratios of folinic acid to MTX of 31 and 6, respectively. The median 5-MTHF level during rescue was 0.44 μmol·l−1 with a median ratio of 5-MTHF to MTX of 2.

Twenty infusions with 48 h MTX levels of less than 0.5 μmol·l−1 were without marked toxicity. Only one patient with a 48 h MTX concentration of 5.5 μmol·l−1 and a ratio of 5-MTHF to MTX of 0.08 suffered from ulcerating mucositis and septicaemia despite increased and prolonged LCV rescue.

Key words

Methotrexate folinic acid 7-hydroxymethotrexate pharmacokinetics 5-methyltetrahydrofolic acid leucovorin 


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Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • C. Wolfrom
    • 1
  • R. Hepp
    • 2
  • R. Hartmann
    • 1
  • H. Breithaupt
    • 2
  • G. Henze
    • 1
  1. 1.Department of PediatricsFreie Universität BerlinFRG
  2. 2.Department of Clinical Pharmacology of the Medical ClinicJustus-Liebig UniversitätGießenFRG

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