Relevance of thiopurine methyltransferase activity in in¯ammatory bowel disease patients maintained on low-dose azathioprine S. CAMPBELL, K. KINGSTONE & S. GHOSH Department of Medical Sciences, University of Edinburgh, Western General Hospital, Edinburgh, UK Accepted for publication 1 October 2001 INTRODUCTION Thiopurine methyltransferase (TPMT) is a cytosolic enzyme that catalyses the S-methylation of aromatic and heterocyclic sulphydryl compounds, including 6-mercaptopurine and azathioprine. The metabolism of 6-mercaptopurine is competitive between TPMT and two other enzymes (xanthine oxidase and hypoxanthine guanine phosphoribosyltransferase). TPMT converts 6-mercaptopurine into an inactive form, 6-methylmer- captopurine, while hypoxanthine guanine phosphori- bosyltransferase converts 6-mercaptopurine into an active form, 6-thioguanine 1 (Figure 1). Azathioprine is generally prescribed in a dose of 2 mg/ kg, although some authorities, especially in the USA, recommend higher doses of 2.5±3.0 mg/kg body weight. In the UK, it is not uncommon to prescribe doses lower than 2 mg/kg body weight, but the relationship of the various dosing regimens to the effectiveness of maintenance with reference to TPMT activity has not been investigated. SUMMARY Background: It is well-recognized that patients with low thiopurine methyltransferase activity are more suscept- ible to the development of bone marrow suppression side-effects. Aim: To study the impact of thiopurine methyltransfer- ase activity on the clinical course of in¯ammatory bowel disease patients treated with low-dose azathioprine (< 2 mg/kg). Methods: We measured the thiopurine methyltransfer- ase activity of blood samples from 113 in¯ammatory bowel disease patients who were taking azathiopurine, had discontinued azathioprine because of side-effects, or had never taken azathioprine. The thiopurine methyl- transferase activity was compared with that of 17 healthy controls. Relapse rates and time to ®rst relapse were compared in in¯ammatory bowel disease patients and strati®ed according to their thiopurine methyl- transferase activity. Results: Patients who became neutropenic had a signi®cantly lower mean thiopurine methyltransferase activity than that of patients who developed other side-effects (analysis of variance, P < 0.05). Survival curves were constructed (time to ®rst relapse) for patients treated with low-dose azathioprine for thio- purine methyltransferase activities of < 20 and > 20 nmol/mL red blood cells/h. There was a signi- ®cantly lower number of relapses in in¯ammatory bowel disease patients with lower thiopurine methyl- transferase levels (P < 0.05). Conclusions: The mean thiopurine methyltransferase activity was signi®cantly lower in patients on a low dose of azathioprine in remission compared with those who relapsed. The thiopurine methyltransferase activity was signi®cantly lower in patients who discontinued azathioprine due to neutropenia than in those who discontinued due to other side- effects. Correspondence to: Dr S. Ghosh, Gastrointestinal Unit, Department of Medical Sciences, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK. E-mail: sg@srv0.med.ed.ac.uk Aliment Pharmacol Ther 2002; 16: 389±398. Ó 2002 Blackwell Science Ltd 389