PHARMACOKINETICS OF METHOTREXATE AND 7-HYDROXYMETHOTREXATE FOLLOWING INFUSIONS OF HIGH-DOSE METHOTREXATE

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  • 1 January 1982
    • journal article
    • research article
    • Vol. 66  (9) , 1733-1741
Abstract
The pharmacokinetics of methotrexate (MXT) and 7-hydroxymethotrexate (7-OH-MTX) were studied in 7 patients treated for osteosarcoma with up to 27 cycles of MTX at doses of 140-350 mg/kg of body wt. The distribution volume of MTX was 0.186 .+-. 0.062 l/kg. Peak plasma levels ranged from 540-1700 .mu.M for MTX and from 12-560 .mu.M for 7-OH-MTX. The MTX metabolite 2,4-diamino-N10-methylpteroic acid was occasionally detectable in plasma and urine at a level of 10-7 M. Plasma disappearance of MTX was biphasic, with a terminal half-life of 2.1 .+-. 0.6 h (mean .+-. SE). Plasma decay of 7-OH-MTX was mainly monoexponential, with a half-life of 23.8 .+-. 15.2 h. The renal clearance of MTX (0.0623 .+-. 0.0232 l/kg per h) accounted for .apprx. 84% of the total clearance of MTX (0.0742 .+-. 0.0288 l/kg per h). In urine, 70%-94% of the dose was recovered as MTX and 0.4%-11% as 7-OH-MTX. The renal clearance of 7-OH-MTX was in the range of 0.0173 .+-. 0.0149 l/kg per h. The pharmacokinetics of MTX and 7-OH-MTX were highly reproducible intraindividually. The kinetics of MTX and 7-OH-MTX were influenced by orally coadministered activated charcoal, presumably by inhibition of enteral reabsorption of MTX and 7-OH-MTX.