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Clinical and experimental pharmacokinetic interaction between 6-mercaptopurine and methotrexate

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Abstract

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/m2 and i.v. infusion of high-dose MTX at 2 or 5 g/m2 once every other week. When 6-MP was given alone, the mean peak plasma concentration (Cmax) and area under the curve (AUC) of 6-MP were 72.5 ng/ml and 225.3 hngml-1. Concurrent treatment with MTX at 2 or 5 g/m2 resulted in a mean increase of 108% and 121% in the Cmax and of 69% and 93% in the AUC, respectively. In rats treated with an oral dose of 6-MP at 75 mg/m2, MTX given i.p. at 5 g/m2 produced mean increases of 110% and 230% in the Cmax 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 ug/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 Cmax and AUC of 6-MP in humans and animals.

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Author notes

  1. Mario Del Tacca

    Present address: Institute of Medical Pharmacology, University of Pisa, Via Roma 55, 1-56126, Pisa, Italy

Authors and Affiliations

  1. Institute of Medical Pharmacology, University of Pisa, Via Roma 55, 1-56126, Pisa, Italy

    Federico Innocenti, Guido Bocci & Denise Nardini

  2. Superior School of University Studies and Doctoral Research S. Anna, Pisa, Italy

    Romano Danesi & Antonello Di Paolo

  3. Institute of Pediatric Clinic, University of Pisa, Pisa, Italy

    Barbara Loru, Claudio Favre, Margherita Nardi & Pierantonio Macchia

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  1. Federico Innocenti
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  2. Romano Danesi
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Innocenti, F., Danesi, R., Di Paolo, A. et al. Clinical and experimental pharmacokinetic interaction between 6-mercaptopurine and methotrexate. Cancer Chemother Pharmacol 37, 409–414 (1996). https://doi.org/10.1007/s002800050405

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  • DOI: https://doi.org/10.1007/s002800050405

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