Pharmacokinetics of oral methotrexate in children.

The absorption and disposition kinetics of p.o. methotrexate were studied in 15 children. Serum levels and urinary excretion of methotrexate, as measured by the dihydrofolate reductase inhibition assay, were monitored following a routine p.o. dose (6.3 to 28.1 mg/sq m) administered after an overnight fast. Significant interindividual variability was noted in peak levels (range, 0.27 to 1.1 microM), time to peak (1 to 5 hr), area under the serum concentration-time curve (1.08 to 5.00 microM . hr), and the fraction of the dose absorbed (23 to 95%). Patients taking doses greater than 12 mg/sq m had a more prolonged absorptive phase and absorbed a smaller fraction of their dose, indicating that the mechanism of absorption may be saturable in some patients within the commonly administered dosage range. Urinary excretion was rapid, and the mean renal clearance of methotrexate was 1.6 times greater than was creatinine clearance, consistent with renal tubular secretion of the drug. While the marked degree of variability observed suggests a potential role for therapeutic drug monitoring in optimizing p.o. methotrexate therapy, the critical time points to monitor, the therapeutic and toxic ranges, and the intrapatient consistency of absorption must be defined before it will be practical and useful.