Pharmacokinetics of methotrexate and 7-hydroxy-methotrexate in plasma and bone marrow of children receiving low-dose oral methotrexate.

The absorption, distribution, and elimination kinetics of low-dose p.o. methotrexate (MTX) were repeatedly studied in 19 children during maintenance treatment of childhood acute lymphoblastic leukemia. Plasma concentrations, urinary elimination, and bone marrow concentrations of MTX and 7-hydroxymethotrexate (7-OH-MTX) were monitored during 24 h following a routine p.o. dose (30 mg/m2) using high-pressure liquid chromatography. Significant interindividual variability was found in time to peak concentration (30-180 min), peak concentration (0.41-2.77 microM), and to a lesser extent the half-lives (t1/2 alpha: 32.8-86.1 min; t1/2 beta: 43.6-350.0 min; t1/2 absorption: 25.2-60.3 min) and plasma area under the concentration-time curve from zero to infinity (195.6-818.5 microM.min). Significant amounts of 7-OH-MTX were detected in plasma, with a mean area under the concentration-time curve from zero to infinity of 208 microM.min compared with 365.6 microM.min for MTX. High concentrations of 7-OH-MTX were present in bone marrow 24 h after oral MTX (15/19 patients) and were at least five fold those in plasma and three fold the concentration of MTX in bone marrow. In four patients occasionally neither MTX nor metabolite could be detected. Repeated examination of these pharmacokinetic parameters in plasma and bone marrow showed that the intraindividual variability was small.