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

• Published in: Alimentary pharmacology & therapeutics Vol. 16; no. 1; pp. 79 - 85
• Main Authors: Dewit, O., Vanheuverzwyn, R., Desager, J. P., Horsmans, Y.
• Format: Journal Article
• Language: English
• Published: Oxford UK Blackwell Science Ltd 01.01.2002; Blackwell
• Subjects: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal - adverse effects; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Azathioprine - adverse effects; Azathioprine - pharmacology; Biological and medical sciences; Biomarkers - analysis; Crohn Disease - drug therapy; Drug Interactions; Drug toxicity and drugs side effects treatment; Female; Guanine Nucleotides - blood; Humans; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - pharmacology; Male; Medical sciences; Mesalamine - adverse effects; Mesalamine - metabolism; Mesalamine - pharmacology; Methyltransferases - metabolism; Middle Aged; Pharmacology. Drug treatments; Sulfasalazine - adverse effects; Sulfasalazine - pharmacology; Thionucleotides - blood; Toxicity: blood; Metabolite; Bone marrow disease; Blood; Inflammatory disease; Blood plasma; Enzymatic activity; Intestinal disease; Aminosalicylic acid; Drug interaction; Thiopurine S-methyltransferase; Salicylates; Human; Drug combination; Immune response; Enzyme; Transferases; Metabolism; Long term; Non steroidal antiinflammatory agent; Crohn disease; Blood cell; Chemotherapy; Treatment; Methyltransferases; Mesalazine; Digestive diseases; Immunosuppressive agent; Azathioprine; Pharmacokinetics
• ISSN: 0269-2813; 1365-2036
• 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 × 108 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.