Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis

Arthritis Rheum. 2008 Nov;58(11):3299-308. doi: 10.1002/art.24034.


Objective: There is evidence supporting a therapeutic range for methotrexate polyglutamate (MTXGlu) concentrations in the treatment of rheumatoid arthritis (RA). Knowledge of the pharmacokinetics of MTXGlu1-5 is required for optimal timing of blood sampling. The aim of this study was to determine the time to steady state and the half-life of accumulation of red blood cell (RBC) MTXGlu1-5 in patients with RA commencing oral MTX, and the time for RBC MTXGlu1-5 to become undetectable and the half-life of elimination of RBC MTXGlu1-5 in patients ceasing treatment with oral MTX.

Methods: Ten patients beginning treatment and 10 patients stopping treatment with low-dose oral MTX were recruited. Blood samples were initially collected weekly, with gradual extension to monthly collection over the study period. RBC MTXGlu1-5 concentrations were assayed by high-performance liquid chromatography. Results were analyzed using a first-order exponential method.

Results: The median times to reach steady state in RBCs (defined as 90% of the maximum concentration) were 6.2, 10.6, 41.2, 149, and 139.8 weeks, respectively, for MTXGlu1, MTXGlu2, MTXGlu3, MTXGlu4, and MTXGlu5. The median half-life of accumulation for RBC MTXGlu1-5 ranged from 1.9 weeks to 45.2 weeks. The median times for MTXGlus to become undetectable in RBCs were 4.5, 5.5, 10, 6, and 4 weeks, respectively, for MTXGlu1, MTXGlu2, MTXGlu3, MTXGlu4, and MTXGlu5. The median half-life of elimination for RBC MTXGlu1-5 ranged from 1.2 weeks to 4.3 weeks.

Conclusion: There is wide interpatient variability of RBC MTXGlu1-5 accumulation and elimination in adults with RA. These data also suggest that after a dose change, >6 months are required for RBC MTXGlu1-5 to reach steady state. Such delays in achieving steady state suggest that more rapid dose escalation or subcutaneous administration from the outset should be considered.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Arthritis, Rheumatoid / drug therapy*
  • Chromatography, High Pressure Liquid
  • Erythrocytes / chemistry
  • Female
  • Half-Life
  • Humans
  • Individuality
  • Male
  • Methotrexate / administration & dosage
  • Methotrexate / analogs & derivatives*
  • Methotrexate / blood
  • Methotrexate / pharmacokinetics
  • Middle Aged
  • Polyglutamic Acid / administration & dosage
  • Polyglutamic Acid / analogs & derivatives*
  • Polyglutamic Acid / blood
  • Polyglutamic Acid / pharmacokinetics


  • Polyglutamic Acid
  • methotrexate polyglutamate
  • Methotrexate