Abstract
Summary Background Up to 20% of patients on thiopurine therapy fail to achieve adequate drug response. Many of these patients preferentially produce the toxic 6‐methylmercaptopurine metabolites (6‐MMP) rather than the active 6‐thioguanine nucleotides (6‐TGN) resulting in a high 6‐MMP/6‐TGN ratio (>20) and increased risk of hepatotoxicity. Aim To determine the prevalence of preferential 6‐MMP producers and define the relationships between 6‐TGN, 6‐MMP and thiopurine methyltransferase (TPMT). Methods The database of 6‐TGN, 6‐MMP and TPMT measurements from patients throughout New Zealand was used to calculate patients’ 6‐MMP/6‐TGN ratios and identify those with high (>20) or normal ratio (≤20).The TPMT enzyme activity was compared amongst the groups. Results Of 1879 patients with TPMT, 6‐TGN and 6‐MMP results, 349 (19%) had a 6‐MMP/6‐TGN ratio >20. The mean TPMT enzyme activity was slightly lower for those with a 6‐MMP/6‐TGN ratio ≤20 vs. >20, which achieved statistical significance (12.2 vs. 13.2; P < 0.001). However, the distributions of TPMT enzyme activity were similar, with 97% of TPMT results falling between 5.0 and 17.6 IU/mL for both groups. In all, 17% of those with 6‐MMP/6‐TGN ratio ≤20 were intermediate TPMT metabolisers (TPMT 5.0–9.2 IU/mL) vs. 7% in those with a ratio >20. Conclusions In this patient population with measured 6‐MMP/6‐TGN ratios, 19% of patients were preferential 6‐MMP producers. The results show that high TPMT enzyme activity is not the major reason for preferential 6‐MMP production in most patients with a high metabolite ratio. This suggests that there are one or more important alternative mechanisms for preferentially producing 6‐MMP.