Pharmacokinetics, dose adjustments, and 6-mercaptopurine/methotrexate drug interactions in two patients with thiopurine methyltransferase deficiency

Acta Paediatr. 1998 Jan;87(1):108-11. doi: 10.1080/08035259850158001.


Two children with acute lymphoblastic leukaemia (ALL) were found to be thiopurine methyltransferase (TPMT)-deficient by both genotype and phenotype. They were monitored with haematological parameters and red blood cell concentrations of 6-thioguanine nucleotides (E-6TGN) and methotrexate (E-MTX, including MTX polyglutamates), in relation to the doses of 6-mercaptopurine (6MP) and methotrexate (MTX), during their maintenance chemotherapy. Both patients developed severe pancytopenia at the standard protocol dose of 6MP. Even at 25% and 5%, respectively, of the protocol dose of 6MP, they achieved E-6TGN values several-fold above the population median, but without unacceptable bone-marrow toxicity. Their high E-6TGN values had only a minor influence on their E-MTX values and their tolerance to oral MTX, but severe pancytopenia followed high-dose MTX infusions. Due to the risk of fatal myelosuppression we recommend up-front determination of TPMT activity in patients treated with 6MP or azathioprine.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics*
  • Child
  • Child, Preschool
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Follow-Up Studies
  • Humans
  • Male
  • Mercaptopurine / administration & dosage
  • Methotrexate / administration & dosage
  • Methyltransferases / deficiency*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / complications
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / diagnosis
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*


  • Mercaptopurine
  • Methyltransferases
  • thiopurine methyltransferase
  • Methotrexate