Clinical and experimental pharmacokinetic interaction between 6-mercaptopurine and methotrexate

Clinical and experimental pharmacokinetic interaction between 6-mercaptopurine (6-MP) and methotrexate (MTX) was investigated in patients as well as in rats and in HL-60 human leukemic cells. Ten children affected by acute lymphoblastic leukemia (ALL) in remission received daily doses of 6-MP given at 25 mg/m(2) and i.v, infusion of high-dose MTX at 2 or 5 g/m(2) once every other week. When 6-MP was given alone, the mean peak plasma concentration (C-max) and area under the curve (AUC) of 6-MP were 72.5 ng/ml and 225.3 h ng ml(-1). Concurrent treatment with MTX at 2 or 5 g/m(2) resulted in a mean increase of 108% and 121% in the C-max and of 69% and 93% in the AUG, respectively. In rats treated with an oral dose of 6-MP at 75 mg/m(2), MTX given i.p. at 5 g/m(2) produced mean increases of 110% and 230% in the C-max and AUC of 6-MP, respectively. In HL-60 human leukemic cells incubated with 6-MP at 250 ng/ml, the cumulative intracellular concentration of 6-thioguanine and 6-MP nucleotides was not significantly modified by treatment with 20 mu g/ml of MTX. The present findings indicate that high-dose MTX enhances the bioavailability of 6-MP as evidenced by the observed increases in the plasma C-max and AUC of 6-MP in humans and animals.