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

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.

Key words

6-Mercaptopurine Pharmacokinetics Methotrexate Lymphoblastic leukemia Rat 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Balis FM, Holcenberg JS, Zimm S, Tubergen D, Collins JM, Murphy RF, Gilchrist GS, Hammond D, Poplack DG (1987) The effect of methotrexate on the bioavailability of oral 6-mercaptopurine. Clin Pharmacol Ther 41:384PubMedGoogle Scholar
  2. 2.
    Bokkerink JP, Bakker MAH, Hulscher TW, De Abreu RA, Schretlen EDAM, Van Laarhoven JPRM, De Bruyn CHMM (1986) Sequence-, time-, and dose-dependent synergism of methotrexate and 6-mercaptopurine in malignant human T-lymphoblasts. Biochem Pharmacol 35:3549PubMedCrossRefGoogle Scholar
  3. 3.
    Bokkerink JP, De Abreu RA, Stet EH, Damen FJ (1992) Cell kinetics and biochemical pharmacology of methotrexate and 6-mercaptopurine in human malignant T-lymphoblasts. Klin Paediatr 204:293CrossRefGoogle Scholar
  4. 4.
    Brunschede H, Krooth RS (1973) Studies on the xanthine oxidase activity of mammalian cells. Biochem Genet 8:341PubMedCrossRefGoogle Scholar
  5. 5.
    Burchenal JH, Murphy ML, Ellison RR, Sykes MP, Tan TC, Leone LA, Karnofsky DA, Craver LF, Dargeon HW, Rhoads CP (1953) Clinical evaluation of a new antimetabolite, 6-mercaptopurine, in the treatment of leukaemia and allied diseases. Blood 8:965PubMedGoogle Scholar
  6. 6.
    Cadman EC, Heimer R, Davis L (1979) Enhanced 5-fluorouracil nucleotide formation after methotrexate administration. Explanation of the drug synergism. Science 205:1135PubMedCrossRefGoogle Scholar
  7. 7.
    Ding TL, Benet LZ (1979) Comparative bioavailability and pharmacokinetic studies of azathioprine and 6-mercaptopurine in the rhesus monkey. Drug Metab Dispos 7:373PubMedGoogle Scholar
  8. 8.
    Frei E, Sailan SE (1978) Acute lymphoblastic leukemia: treatment. Cancer 42:828PubMedCrossRefGoogle Scholar
  9. 9.
    Hayder S, Lafolie P, Bjork O, Peterson C (1989) 6-Mercaptopurine plasma levels in children with acute lymphoblastic leukemia: relation to relapse risk and myelotoxicity. Ther Drug Monit 11:617PubMedCrossRefGoogle Scholar
  10. 10.
    Koren G, Feraazini G, Sulh H, Langerin AM, Kapelushnik J, Klein J, Giesbrecht E, Soldin S, Greenberg M (1990) Systemic exposure to mercaptopurine as a prognostic factor in acute lymphoblastic leukemia in children. N Engl J Med 323:17PubMedCrossRefGoogle Scholar
  11. 11.
    Kurowsky V, Iven H (1991) Plasma concentrations and organ distribution of thiopurines after oral application of azathioprine in mice. Cancer Chemother Pharmacol 28:7CrossRefGoogle Scholar
  12. 12.
    Lafolie P, Hayder S, Bjork O, Ahstrom L, Liliemark J, Peterson C (1986) Large interindividual variations in the pharmaco-kinetics of oral 6-mercaptopurine in maintenance therapy of children with acute leukemia and non-Hodgkins lymphoma. Acta Paediatr Scand 75:797PubMedCrossRefGoogle Scholar
  13. 13.
    Lennard L (1992) The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol 43:329PubMedCrossRefGoogle Scholar
  14. 14.
    Lennard L, Lilleyman JS (1989) Variable mercaptopurine metabolism and treatment outcome in childhood lymphoblastic leukemia. J Clin Oncol 7:1816PubMedGoogle Scholar
  15. 15.
    Lennard L, Maddocks J (1983) Assay of 6-thioguanine nucleotide, a major metabolite of azathioprine, 6-mercaptopurine and 6-thioguanine, in human red blood cells. J Pharm Pharmacol 35:15PubMedGoogle Scholar
  16. 16.
    Lennard L, Singleton HJ (1992) High-performance liquid Chromatographic assay of the methyl and nucleotide metabolites of 6-mercaptopurine: quantitation of red blood cell 6-thioguanine nucleotide, 6-thioinosinic acid and 6-methylmer-captopurine metabolites in a single sample. J Chromatogr 583:83PubMedCrossRefGoogle Scholar
  17. 17.
    Lennard L, Keen D, Lilleyman JS (1986) Oral 6-mercaptopurine in childhood leukemia: parent drug pharmacokinetics and active metabolite concentrations. Clin Pharmacol Ther 40:287PubMedGoogle Scholar
  18. 18.
    Lennard L, Lilleyman JS, Van Loon J, Weinshilboum RM (1990) Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukemia. Lancet 336:225PubMedCrossRefGoogle Scholar
  19. 19.
    Lewis AS, Murphy L, McCalla C, Fleary M, Purcell S (1984) Inhibition of mammalian xanthine oxidase by folate compounds and amethopterin. J Biol Chem 259:12PubMedGoogle Scholar
  20. 20.
    Lin S-N, Jessup K, Floyd M, Wang T-PF, Van Buren CT, Caprioli RM, Kahan BD (1980) Quantitation of azathioprine and 6-mercaptopurine levels in renal transplant patients. Transplantation 29:290PubMedCrossRefGoogle Scholar
  21. 21.
    Lockhart S, Plunkett W, Jeha S, Ramirez I, Zipf T, Cork A, Pinkel D (1994) High-dose mercaptopurine followed by intermediate-dose cytarabine in relapsed acute leukemia. J Clin Oncol 12:587PubMedGoogle Scholar
  22. 22.
    Maddocks J (1979) Assay of azathioprine, 6-mercaptopurine and a novel thiopurine metabolite in human plasma. Br J Clin Pharmacol 8:273PubMedGoogle Scholar
  23. 23.
    Morgan CJ, Chawdry RN, Smith A, Siravo-Sagraves G, Trewyn RW (1994) 6-thioguanine-induced growth arrest in 6-mercaptopurine-resistant human leukemia cells. Cancer Res 54:5387PubMedGoogle Scholar
  24. 24.
    Pennington AM, Bronk JR (1995) The absorption of 6-mercaptopurine from 6-mercaptopurine riboside in rat small intestine: effect of phosphate. Cancer Chemother Pharmacol 36:136PubMedCrossRefGoogle Scholar
  25. 25.
    Poplack DG (1985) Acute lymphoblastic leukemia in children. Pediatric Clin North Am 32:669Google Scholar
  26. 26.
    Riccardi R, Balis F, Ferrara P, Lasorella A, Poplack D, Mastrangelo R (1986) Influence of food intake on bioavailability of oral 6-mercaptopurine in children with acute lymphoblastic leukemia. Pediatr Hematol Oncol 3:319PubMedCrossRefGoogle Scholar
  27. 27.
    Rivera G, Raimondi S, Hancock M (1991) Improved outcome in childhood acute lymphoblastic leukemia with reinforced early treatment and rotational combination chemotherapy. Lancet 337:61PubMedCrossRefGoogle Scholar
  28. 28.
    Simone JV (1980) The treatment of acute lymphoblastic leukemia. Br J Haematol 45:1PubMedCrossRefGoogle Scholar
  29. 29.
    Spreafico F, Donelli MG, Bossi A, Vecchi A, Standen S, Garattini S (1973) Immunodepressant activity and 6-mercaptopurine levels after administration of 6-mercaptopurine and azathioprine. Transplantation 16:269PubMedCrossRefGoogle Scholar
  30. 30.
    Stet EH, De Abreu RA, Bokkerink JP, Lambooy LHJ, Vogels-Mentink TM, Keizer-Garritsen JJ, Trijbels FJM (1995) Reversal of methylmercaptopurine ribonucleoside cytotoxicity by purine ribonucleosides and adenine. Biochem Pharmacol 49:49PubMedCrossRefGoogle Scholar
  31. 31.
    Sulh H, Koren G, Whalen C, Soldin S, Zipursky A, Greenberg M (1986) Pharmacokinetic determinations of 6-mercaptopurine myelotoxicity and therapeutic failure in children with acute lymphoblastic leukemia. Clin Pharmacol Ther 40:604PubMedGoogle Scholar
  32. 32.
    Tubergen D, Gulchrist G, Coccia P (1991) The interaction of central nervous system (CNS) therapy and systemic therapy in the prevention of CNS relapse in acute lymphoblastic leukemia (ALL). Proc Am Soc Clin Oncol 10:233Google Scholar
  33. 33.
    Warren DJ, Andersen A, Slordal L (1995) Quantitation of 6-thioguanine residues in peripheral blood leukocyte DNA obtained from patients receiving 6-mercaptopurine-based maintenance therapy. Cancer Res 55:1670PubMedGoogle Scholar
  34. 34.
    Whalen CE, Tamary H, Greemberg M, Zipursky A, Soldin SJ (1985) Analysis of 6-mercaptopurine in serum or plasma using high performance liquid chromatography. Ther Drug Monit 7:315PubMedCrossRefGoogle Scholar
  35. 35.
    Zimm S, Collins JM, O’Neill D, Chabner BA, Poplack DG (1983) Inhibition of first-pass metabolism in cancer chemotherapy: interaction of 6-mercaptopurine and allopurinol. Clin Pharmacol Ther 34:810PubMedGoogle Scholar
  36. 36.
    Zimm S, Collins JM, Riccardi R, O’Neill D, Narang PK, Chabner B, Poplack DG (1983) Variable bioavailability of oral mercaptopurine: is maintenance chemotherapy in acute lymphoblastic leukemia being optimally delivered? N Engl J Med 308:1005PubMedGoogle Scholar

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

Personalised recommendations