Pharmacokinetics of methotrexate and 7-hydroxymethotrexate following infusions of high-dose methotrexate.
The pharmacokinetics of methotrexate (MXT) and 7-hydroxymethotrexate (7-OH-MTX) has been studied in seven patients treated for osteosarcoma with up to 27 cycles of MTX at doses of 140-350 mg/kg of body weight. The distribution volume of MTX was 0.186 +/- 0.062 liter/kg. Peak plasma levels ranged from 540 to 1700 microM for MTX and from 12 to 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 hours (mean +/- SE). Plasma decay of 7-OH-MTX was mainly monoexponential, with a half-life of 23.8 +/- 15.2 hours. The renal clearance of MTX (0.0623 +/- 0.0232 liter/kg/hour) accounted for about 84% of the total clearance of MTX (0.0742 +/- 0.0288 liter/kg/hour). 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 liter/kg/hour. The pharmacokinetics of MTX and 7-OH-MTX was influenced by orally coadministered activated charcoal, presumably by inhibition of enteral reabsorption of MTX and 7-OH-MTX.
D000293:Adolescent; D000328:Adult; D001646:Bile / Q000378:metabolism; D001859:Bone Neoplasms; D002606:Charcoal / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D005750:Gastric Juice / Q000032:analysis; D006207:Half-Life; D006801:Humans; D007263:Infusions, Parenteral; D007700:Kinetics; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000378:metabolism*; D008875:Middle Aged; D012516:Osteosarcoma
D002606:Charcoal; C011864:7-hydroxymethotrexate; D008727:Methotrexate