Interaction between trimethoprim-sulfamethoxazole and methotrexate in children with leukemia

J Pediatr. 1990 Nov;117(5):823-6. doi: 10.1016/s0022-3476(05)83351-7.


Because trimethoprim-sulfamethoxazole (TMP-SMX) causes neutropenia in children with leukemia, we investigated the possibility that pharmacokinetic interaction between methotrexate (MTX) and TMP-SMX causes accumulation of the antileukemia agent. We studied the pharmacokinetics of MTX given intravenously or orally to nine children with acute lymphoblastic leukemia, once with and once without TMP-SMX. There was an increase in free MTX fraction during TMP-SMX therapy in all patients, from (mean +/- SD) 37.4 +/- 11% without TMP-SMX to 52.2 +/- 6.4% with TMP-SMX (p less than 0.01). Plasma clearance of total MTX did not change significantly, whereas clearance of free MTX decreased significantly (from 12.5 +/- 4 to 7.6 +/- 1.5 ml/kg/min; p less than 0.05). There was a consistent decrease in the renal clearance of free MTX (from 12.1 +/- 6.8 to 5.6 +/- 2.4 ml/kg/min; p less than 0.05). Elimination half-life of MTX was not affected significantly by TMP-SMX. There was a significant correlation between serum concentrations of TMP-SMX and the percentage of decrease in the renal clearance of free MTX (r = 0.91; p less than 0.05). These changes in protein binding and tubular clearance of MTX, caused by competition with TMP-SMX, result in a mean 66% increase in systemic exposure to MTX and may explain the myelotoxicity often observed with the coadministration of the two drugs.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Marrow / drug effects
  • Child
  • Child, Preschool
  • Drug Interactions
  • Female
  • Half-Life
  • Humans
  • Male
  • Methotrexate / adverse effects
  • Methotrexate / pharmacokinetics*
  • Methotrexate / therapeutic use
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Protein Binding
  • Trimethoprim, Sulfamethoxazole Drug Combination / adverse effects
  • Trimethoprim, Sulfamethoxazole Drug Combination / pharmacokinetics*
  • Trimethoprim, Sulfamethoxazole Drug Combination / therapeutic use


  • Trimethoprim, Sulfamethoxazole Drug Combination
  • Methotrexate