Dubinsky et al.[22] demonstrated a correlation between 6TGN levels and remission, as well as a correlation between higher 6TGN levels and leucopenia. This correlation has also been documented in pediatric acute lymphoblastic leukemia[35] as well as heart and renal transplantation literature.[36, 37] High 6TGN

levels have also been associated with an increased risk of any adverse event. In a retrospective Selleckchem Pifithrin �� Swedish study of 364 IBD patients, 41% of patients with a 6TGN above 400 experienced an adverse event (P = 0.005), including myelotoxicity and gastrointestinal disturbances.[38] Prior to the advent of thiopurine metabolite testing, standard clinical practice suggested that, if a patient on thiopurine therapy develops hepatotoxicity

(as evidenced by elevated transaminases and/or cholestatic enzymes with or without a rise in bilirubin), the offending agent should be withdrawn and a patient should be labelled as having an ‘allergy’ to thiopurines. As such, thiopurines could no longer be considered as a potential therapeutic option again for that patient. The Canadian group that originally discovered the minimum therapeutic threshold for 6TGN found that high levels of 6MMP were associated with hepatotoxicity in the form of elevated levels of hepatic transaminases. In total, 16 of 92 patients (17%) developed hepatotoxicity. Median 6MMP levels in patients with hepatotoxicity were 5463, compared with 2213 for those with normal liver enzymes. If 6MMP levels were above 5700, the risk of hepatotoxicity EPZ6438 increased by a factor of three (18% vs. 6%). There was no correlation with 6MMP levels and therapeutic response or 6MP dose. There was also no correlation between 6TGN levels and hepatotoxicity.[22] triclocarban Patients who preferentially

produce 6MMP rather than 6TGN are known as ‘thiopurine shunters’ (see below). This group, characterized by having a 6MMP to 6TGN ratio > 20, is at risk for hepatotoxicity and possibly refractoriness to standard thiopurine therapy. There are two major drug interactions with thiopurines with direct relevance to metabolite testing. The first is with allopurinol, a potent inhibitor of XO, one of the critical enzymes involved in thiopurine metabolism. Allopurinol has been the mainstay of treatment for gout for many years.[39] Traditional teaching has dictated that because the combination of full dose allopurinol and thiopurines causes profound myelosuppression, the two drugs should never be given in combination.[38] More recently, the effect of allopurinol on thiopurine metabolism is being used to advantage (see below). The second interaction is with 5-aminosalicylates (balsalazide, mesalasine, olsalazine or sulphasalazine), used frequently in IBD patients and sometimes in rheumatological conditions. Studies in vitro have shown that sulphasalazine and olsalazine can inhibit TPMT,[40, 41] suggesting that concomitant 5ASA may increase 6TGN levels and potentially lead to myelosuppression.