Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease A. ANSARI  , C. HASSAN  , J. DULEY à , A. MARINAKI à , E. -M. SHOBOWALE-BAKRE à , P. SEED*, J. MEENAN  , A. YIM  & J. SANDERSON   *Department of Public Health Medicine, GKT School of Medicine, London, UK;  Department of Gastroenterology and àPurine Research Laboratory, Guy’s and St Thomas’ Hospitals Trust, London, UK Accepted for publication 1 July 2002 SUMMARY Background: Azathioprine therapy is discontinued in one-third of patients with inflammatory bowel disease because of toxicity or a lack of clinical response. Patients with thiopurine methyltransferase (TPMT) deficiency are intolerant to azathioprine, whilst carriers are at increased risk of side-effects. Aim: To evaluate the importance of TPMT activity in the management of azathioprine therapy in inflammatory bowel disease. Methods: Clinical response, adverse effects and haema- tological parameters were determined and correlated with TPMT enzyme activity and genotype in 106 patients with inflammatory bowel disease. Results: Ninety-six patients had high TPMT activity, and 10 had intermediate activity. Nineteen patients (18%) were intolerant to azathioprine. Fifteen (16%) of those with high TPMT activity were intolerant, compared with five (50%) with intermediate activity [odds ratio (OR), 5.4; 95% confidence interval (CI), 1.5–19.8]. Complete remission was achieved in 63% of cases, and complete or partial remission in 79%. Interestingly, very high TPMT activity (> 14 units ⁄ mL red blood cells) was significantly associated with non-response, irrespective of the time on azathioprine (OR, 0.21; 95% CI, 0.07– 0.68). TPMT gene mutations correlated with TPMT activity. Conclusions: Inflammatory bowel disease patients with intermediate TPMT activity have an increased risk of azathioprine toxicity. Conversely, very high TPMT activity predicts treatment failure. TPMT genotype predicted TPMT phenotype in this study. I NTRODUCTION The immunosuppressant azathioprine (AZA) is cur- rently one of the most useful drugs in the management of inflammatory bowel disease, with clinical benefit in up to two-thirds of patients. 1 However, in one-third, treatment with AZA is withdrawn either as a result of toxicity (predominantly nausea, pancreatitis and bone marrow suppression) or a lack of clinical response. 2–4 Such cases require either surgery or alternative immu- nosuppressive or biological therapy with greater poten- tial toxicity. Previous studies on patients affected by leukaemia have shown that both toxicity and therapeutic response can be explained, at least in part, by the complex pharmacokinetics of this drug. 5 After oral administra- tion, AZA is immediately converted to 6-mercaptopu- rine. This is either inactivated by xanthine oxidase and thiopurine methyltransferase (TPMT) or activated to cytotoxic 6-thioguanine nucleotides by a multienzy- matic process. 5 Deficiency of TPMT or xanthine oxidase results in a greater conversion of the drug to active Correspondence to: Dr J. Sanderson, Department of Gastroenterology, 1st Floor College House, St Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, UK. E-mail: Jeremy.Sanderson@gstt.sthames.nhs.uk Aliment Pharmacol Ther 2002; 16: 1743–1750. doi:10.1046/j.0269-2813.2002.01353.x Ó 2002 Blackwell Science Ltd 1743