THIOPURINE METHYLTRANSFERASE ACTIVITY IS CORRELATED WITH AZATHIOPRINE METABOLITE LEVELS IN INFLAMMATORY BOWEL DISEASE PATIENTS IN CLINICAL GASTROENTEROLOGY PRACTICE

Abstract

Purpose: Genetic polymorphisms in thiopurine methyltransferase (TPMT) influence the metabolism of azathioprine (AZA) and 6-mercaptopurine (6-MP) in patients with inflammatory bowel disease (IBD). It has been suggested in studies using weight-based dosing that higher TPMT activity is associated with lower levels of 6-thioguanine (6-TG), the metabolite thought to provide therapeutic benefit, and higher levels of 6-methylmercaptopurine (6-MMP), the metabolite associated with hepatotoxicity. Some studies suggest that higher TPMT activity correlates with lower rates of clinical response. The aim of this study is to assess the relationship between TPMT activity and 6-TG and 6-MMP levels in patients with IBD in clinical practice. Methods: We analyzed the TPMT activity, the 6-TG level, and the 6-MMP level in all patients who had at least one TPMT assessment and at least two metabolite profiles sent from a gastroenterologist's office to Prometheus Laboratories (San Diego, CA) from June 2000 to February 2004. The use of AZA or 6-MP and the dosing of the drug was at the discretion of the patient's gastroenterologist. Linear regression was used to analyze the relationships and a Pearson correlation was calculated. Results: A total of 1,020 patients were identified. Linear regression showed a significant inverse relationship between TPMT activity and 6-TG level with a Pearson correlation of-0.162 (p <0.01), a significant direct relationship between TPMT activity and 6-MMP level with a Pearson correlation of 0.172 (p <0.01), and a significant direct relationship between TPMT activity and 6-MMP/6-TG ratio with a Pearson correlation of 0.141 (p <0.01). Conclusions: Higher TPMT activity is associated with lower 6-TG levels and higher 6-MMP levels in IBD patients treated with AZA or 6-MP in clinical practice with drug dosing at the discretion of the primary gastroenterologist. This suggests a possible role for TPMT activity assays in patients being considered for treatment with these agents.