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BACKGROUND AND AIMS: Therapeutic drug monitoring of active metabolites of thiopurines, azathioprine and 6-mercaptopurine, is relatively new. The proposed therapeutic threshold level of the active 6-thioguanine nucleotides (6-TGN) is >/=235pmol/8x10(8) erythrocytes. The aim of this prospective cross-sectional study was to compare 6-TGN levels in adult thiopurine tolerant IBD patients with an exacerbation with those in remission, and to determine the therapeutic 6-TGN cut-off level. METHODS: Hundred IBD patients were included. Outcome measures were thiopurine metabolite levels, calculated therapeutic 6-TGN cut-off level, CDAI/CAI scores, thiopurine dose and TPMT enzyme activity. RESULTS: Forty-one patients had an exacerbation, 59 patients were in remission. In 17% of all patients 6-TGN levels were compatible with non-compliance. The median 6-TGN levels were not significantly different between the exacerbation and remission group (227 versus 263pmol/8x10(8) erythrocytes, p=0.29). The previous reported therapeutic 6-TGN cut-off level of 235pmol/8x10(8) erythrocytes was confirmed in this study. Twenty-six of the 41 patients (63%) with active disease had 6-TGN levels below this threshold and 24 of 59 IBD patients (41%) in clinical remission (p=0.04). CONCLUSIONS: Thiopurine non-compliance occurs frequently both in active and quiescent disease. 6-TGN levels below or above the therapeutic threshold are associated with a significant higher chance of IBD exacerbation and remission, respectively. These data support the role of therapeutic drug monitoring in thiopurine maintenance therapy in IBD to reveal non-compliance or underdosing, and can be used as a practical tool to optimize thiopurine therapy, especially in case of thiopurine non-response.