Dose-dependent kinetics of orally administered 6-mercaptopurine in children with leukemia

To determine whether the pharmacokinetics of 6-mercaptopurine (6-MP) would show dose dependency, we studied three different single oral doses in eight children (aged 3.6 to 15.1 years) with acute leukemia in remission. Marked interindividual differences in maximum plasma concentration (C_max) and the area under the plasma concentration-time curve (AUC) were observed when children received the 50 mg/m² dose. This variability decreased when the doses were increased. Six of the eight children showed a disproportionate increase in the AUC with increasing doses; the other two had a proportionate relationship between the AUC and dose. Overall mean (±SD) C_max and AUC values increased disproportionately (88±123, to 326±194, to 653±344 ng/ml for C_max, and 147±180, to 451±177, to 1291±415 ng/ml per hour for AUC, respectively) when the dose increased from 50 to 87.5 mg/m² and then to 175 mg/m². The results suggest that a saturable first-pass metabolism of oral 6-MP occurs with increasing oral doses in some, but not all, children. Whether and to what extent this pharmacokinetic character of oral 6-MP affects the interindividual difference in systemic exposure to the drug in children with leukemia receiving maintenance therapy require further studies.