Cancer Chemotherapy and Pharmacology

, Volume 37, Issue 5, pp 409–414 | Cite as

Clinical and experimental pharmacokinetic interaction between 6-mercaptopurine and methotrexate

  • Federico Innocenti
  • Romano Danesi
  • Antonello Di Paolo
  • Barbara Loru
  • Claudio Favre
  • Margherita Nardi
  • Guido Bocci
  • Denise Nardini
  • Pierantonio Macchia
  • Mario Del Tacca
Original Article


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.

Key words

6-Mercaptopurine Pharmacokinetics Methotrexate Lymphoblastic leukemia Rat 


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Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • Federico Innocenti
    • 1
  • Romano Danesi
    • 2
  • Antonello Di Paolo
    • 2
  • Barbara Loru
    • 3
  • Claudio Favre
    • 3
  • Margherita Nardi
    • 3
  • Guido Bocci
    • 1
  • Denise Nardini
    • 1
  • Pierantonio Macchia
    • 3
  • Mario Del Tacca
    • 1
  1. 1.Institute of Medical PharmacologyUniversity of PisaPisaItaly
  2. 2.Superior School of University Studies and Doctoral Research S. AnnaPisaItaly
  3. 3.Institute of Pediatric ClinicUniversity of PisaPisaItaly

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