Azathioprine is a medicine that calms the immune system (immunosuppressant). It is used to prevent rejection of transplanted organs and to treat autoimmune diseases such as rheumatoid arthritis, lupus or inflammatory bowel disease. The effect takes weeks to months to appear and requires regular blood monitoring.
Also known as: Imuran
Mesalazine may potentiate azathioprine myelosuppression (TPMT inhibition).
The mesalazine label documents the combination with "Azathioprine or 6-Mercaptopurine: increased risk of blood dyscrasias; monitor complete blood cell counts and platelet counts" (section 7.2). The mechanism is inhibition of thiopurine methyltransferase (TPMT) by aminosalicylates (mesalazine and sulfasalazine), which reduces the inactivating methylation of 6-mercaptopurine (the active metabolite of azathioprine) and shifts metabolism towards the more myelotoxic 6-thioguanine pathway. This interaction is well known in gastroenterology practice (inflammatory bowel disease), where azathioprine and mesalazine are often coadministered. Reduce the azathioprine dose by 25–50% and monitor blood counts weekly during the first month, then monthly; watch for leucopenia, thrombocytopenia and infectious symptoms.
Azathioprine + mesalazine: mesalazine inhibits TPMT and raises active 6-thioguanine levels — additive myelotoxicity. Monitor blood counts.
Mesalazine inhibits thiopurine methyltransferase (TPMT), raising active 6-thioguanine levels.
Periodic full blood count, especially in the first weeks.
Leucopenia, thrombocytopenia, serious infections.
Monitor the blood count regularly; watch for infection and bruising.
DailyMed (FDA) — approved Mesalazine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=47b5d1ee-b439-4ccb-9b01-c0875ccd748a ; approved Azathioprine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5116b22b-1460-5535-e063-6394a90acbe5 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Sulfasalazine, like mesalazine, may inhibit TPMT and increase azathioprine toxicity.
Sulfasalazine (like mesalazine, its active metabolite) inhibits TPMT, the enzyme that inactivates 6-mercaptopurine — the active metabolite of azathioprine. TPMT inhibition shifts metabolism towards 6-thioguanine production, increasing the risk of myelosuppression (leucopenia, thrombocytopenia, anaemia). This interaction is classic in inflammatory bowel disease (IBD), where azathioprine is an immunomodulator and sulfasalazine is anti-inflammatory — both used simultaneously in moderate to severe IBD. The sulfasalazine label does not directly mention azathioprine, but the TPMT mechanism is established in the literature and documented in the azathioprine label (metabolism via TPMT). Monitor blood counts weekly during the first month, then monthly; reduce the azathioprine dose by 25–50% when starting the aminosalicylate; watch for signs of infection and anaemia.
Azathioprine + sulfasalazine: TPMT inhibition by sulfasalazine — risk of additive myelotoxicity. Monitor blood counts and reduce azathioprine dose.
TPMT inhibition by sulfasalazine with increased active azathioprine metabolites.
Periodic blood count.
Myelosuppression.
Monitor blood count and azathioprine dose.
DailyMed (FDA) — approved Sulfasalazine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d967092f-9685-446b-b7b8-17821e29417b ; approved Azathioprine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5116b22b-1460-5535-e063-6394a90acbe5 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Severe myelosuppression. Allopurinol inhibits Azathioprine metabolism, with risk of severe leucopenia and infections.
Azathioprine is an inactive prodrug converted to 6-mercaptopurine, which is then metabolised by xanthine oxidase to inactive thiouric acid. Allopurinol inhibits xanthine oxidase and shifts metabolism towards cytotoxic 6-thioguanine nucleotides: the consequence is accumulation of active metabolites with severe, sometimes fatal, myelosuppression. The approved azathioprine label recommends reducing the dose to one quarter of the usual dose when allopurinol is added. Monitor the blood count frequently (weekly in the first weeks) and adjust the dose based on neutrophils and platelets; also monitor liver function.
Xanthine oxidase inhibitor + azathioprine: allopurinol blocks azathioprine metabolism and greatly raises its levels, with risk of severe myelosuppression and infections. If unavoidable, reduce azathioprine to about 25% of the dose and monitor the blood count.
Xanthine oxidase (inhibited by Allopurinol) inactivates the active metabolite 6-mercaptopurine.
Full blood count every 1–2 weeks when starting the combination.
Fever, recurrent infections, sore throat, spontaneous bruising.
Reduce Azathioprine to about 25% of the usual dose and monitor the full blood count.
DailyMed/FDA (NIH/NLM) — approved Allopurinol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b6c5b5c0-b1cb-44c0-a849-5d317e6fa300 ; approved Azathioprine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5116b22b-1460-5535-e063-6394a90acbe5
Xanthine oxidase inhibitor + azathioprine: risk of severe, potentially fatal marrow suppression.
Like allopurinol, febuxostat inhibits xanthine oxidase and blocks the inactivation of 6-mercaptopurine derived from azathioprine, markedly increasing the cytotoxic 6-thioguanine metabolites — the approved febuxostat label formally contraindicates co-administration with azathioprine or mercaptopurine due to the risk of severe and potentially fatal myelosuppression. There is no documented safe dose; if azathioprine therapy is indispensable, another urate-lowering agent should be chosen and, failing that, a marked azathioprine dose reduction with very close haematological monitoring should be discussed.
Xanthine oxidase inhibitor + azathioprine: risk of severe and potentially fatal myelosuppression. Febuxostat is contraindicated with azathioprine — do not combine; choose an alternative urate-lowering agent.
Febuxostat (like allopurinol) inhibits xanthine oxidase, the enzyme that degrades the active 6-mercaptopurine from azathioprine; levels rise markedly.
Weekly full blood count in the first weeks of the combination.
Fever, severe infections, pancytopenia, bleeding.
Combination contraindicated. Reduce azathioprine dose by about 75% only if clinically essential, with tight full blood count monitoring.
DailyMed (FDA) — approved Azathioprine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5116b22b-1460-5535-e063-6394a90acbe5 ; approved Febuxostat label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f2c338dc-5bab-49f4-a4ac-d8dea8afeea5 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Taking with food reduces nausea.
Take with food to improve tolerance.
EMC-UK (MHRA) — approved Azathioprine SmPC: https://www.medicines.org.uk/emc/product/14296/smpc
Azathioprine may cause hepatotoxicity.
Monitor liver function on therapy.
EMC-UK (MHRA) — approved Azathioprine SmPC: https://www.medicines.org.uk/emc/product/14296/smpc
Thiopurine methyltransferase (TPMT) deficiency predisposes to severe marrow suppression.
Test TPMT before starting; contraindicated in complete deficiency.
EMC-UK (MHRA) — approved Azathioprine SmPC: https://www.medicines.org.uk/emc/product/14296/smpc
Used in specific settings (transplants, autoimmune diseases) when benefit outweighs risk.
Keep only under specialist supervision; do not start without clear indication.
Limited data; prefer to avoid, though sometimes kept in transplanted mothers.
Plan pregnancy with the specialist team before stopping/continuing.
EMC-UK (MHRA) — approved Azathioprine SmPC: https://www.medicines.org.uk/emc/product/14296/smpc
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Immunosuppressive antimetabolite: inhibits purine synthesis (via 6-thioguanine) and lymphocyte proliferation, suppressing cell-mediated hypersensitivities and altering antibody production. The magnitude and duration of clinical effects correlate with thiopurine nucleotide levels in tissues, not with plasma levels.
Azathioprine is a prodrug of 6-mercaptopurine (6-MP). 6-MP is activated by hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and kinases to 6-thioguanine nucleotides (6-TGNs), whose incorporation into DNA is responsible for cytotoxicity. The main inactivation routes are thiol methylation by TPMT and oxidation by xanthine oxidase.
Azathioprine is well absorbed following oral administration, with peak serum radioactivity 1–2 hours after the dose. Azathioprine and mercaptopurine are moderately bound to serum proteins (~30%) and are partially dialysable.
Azathioprine is well absorbed; maximum serum radioactivity occurs 1–2 hours after an oral dose. It is metabolised to 6-mercaptopurine and then oxidised or methylated in erythrocytes and the liver — it is undetectable in urine after 8 hours. TPMT or NUDT15 deficiency greatly increases 6-TGN levels and the risk of myelosuppression.
Total radioactivity (drug + labelled metabolites) decays with a half-life of ~5 hours — not an estimate of the half-life of azathioprine itself, but the decay rate for all 35S-containing metabolites. Usual doses produce low blood levels (<1 mcg/mL).
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
