ISSN:
1432-1041
Keywords:
Methotrexate
;
folinic acid
;
7-hydroxymethotrexate
;
pharmacokinetics
;
5-methyltetrahydrofolic acid
;
leucovorin
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
,
Medicine
Notes:
Summary 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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00315414
