Interaction between azathioprine and aminosalicylates: an in vivo study in patients with Crohn's disease

Aliment Pharmacol Ther. 2002 Jan;16(1):79-85. doi: 10.1046/j.1365-2036.2002.01156.x.


Background: The inhibition of thiopurine methyltransferase activity, one of the enzymes responsible for azathioprine metabolism, by aminosalicylates has been described in an in vitro study. This could result in a higher risk of bone marrow depression when using the two drugs together.

Aim: To investigate the in vivo interaction between azathioprine and aminosalicylates in quiescent Crohn's disease by measuring 6-thioguanine nucleotide levels, thiopurine methyltransferase activity and the plasma levels of the acetylated metabolite of 5-aminosalicylic acid.

Methods: Sixteen patients taking a stable dose of azathioprine, plus sulfasalazine or mesalazine, were enrolled and completed the study. They were not taking any drugs interfering with azathioprine metabolism. Four visits every 4 weeks were held over a 3-month period. Aminosalicylate administration was withdrawn after the second visit. At each visit, the blood cell count, inflammatory parameters, levels of 6-thioguanine nucleotide and the acetylated metabolite of 5-aminosalicylic acid and thiopurine methyltransferase activity were determined.

Results: After aminosalicylate withdrawal, mean 6-thioguanine nucleotide levels decreased significantly from 148 pmol (57-357 pmol) to 132 pmol (56-247 pmol) per 8 x 10(8) red blood cells (P=0.027), without significant changes in thiopurine methyltransferase activity or biological parameters.

Conclusions: This in vivo study favours the existence of an interaction between azathioprine and aminosalicylates through a mechanism which remains unclear. This drug-drug interaction should be taken into account when using azathioprine and aminosalicylates simultaneously.

Publication types

  • Clinical Trial

MeSH terms

  • Adult
  • Aged
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects*
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Azathioprine / adverse effects*
  • Azathioprine / pharmacology*
  • Biomarkers / analysis
  • Crohn Disease / drug therapy*
  • Drug Interactions
  • Female
  • Guanine Nucleotides / blood*
  • Humans
  • Immunosuppressive Agents / adverse effects*
  • Immunosuppressive Agents / pharmacology*
  • Male
  • Mesalamine / adverse effects*
  • Mesalamine / metabolism
  • Mesalamine / pharmacology*
  • Methyltransferases / metabolism*
  • Middle Aged
  • Sulfasalazine / adverse effects*
  • Sulfasalazine / pharmacology*
  • Thionucleotides / blood*


  • Anti-Inflammatory Agents, Non-Steroidal
  • Biomarkers
  • Guanine Nucleotides
  • Immunosuppressive Agents
  • Thionucleotides
  • 6-thioguanylic acid
  • Sulfasalazine
  • Mesalamine
  • Methyltransferases
  • thiopurine methyltransferase
  • Azathioprine