Allopurinol might improve response to azathioprine and 6-mercaptopurine by correcting an unfavorable metabolite ratio

Background and Aim: Allopurinol potentiates azathioprine and 6-mercaptopurine (6-MP) by increasing 6-thioguanine nucleotide (6-TGN) metabolite concentrations. The outcome might also be improved by adding allopurinol in individuals who preferentially produce 6-methylmercaptopurine nucleotides (6-MMPN), rather than 6-TGN. The aim of the present study was to investigate the effect of allopurinol on concentrations of 6-MMPN and 6-TGN in individuals with a high ratio of these metabolites (> 20), which is indicative of a poor thiopurine response. Methods: Sixteen individuals were identified who were taking azathioprine or 6-MP, and were commenced on allopurinol to improve a high 6-MMPN : TGN ratio. Metabolite concentrations were compared before and after commencing allopurinol, and markers of disease control were compared. Results: The addition of 100-300 mg allopurinol daily and thiopurine dose reduction (17-50% of the original dose) resulted in a reduction of the median (and range) 6-MMPN concentration, from 11 643 (3 365-27 832) to 221 (55-844) pmol/8 x 108 red blood cells (RBC; P = 0.0005), increased 6-TGN from 162 (125-300) to 332 (135-923) pmol/8 x 108 RBC (P = 0.0005), and reduced the 6-MMPN : 6-TGN ratio from 63 (12-199) to 1 (0.1-4.5) (P = 0.0005). There was a significant reduction in steroid dose requirements at 12 months (P = 0.04) and trends for improvement in other markers of disease control. One patient developed red cell aplasia that resolved upon stopping azathioprine and allopurinol. Conclusions: In those with a high 6-MMPN : 6-TGN ratio (> 20), response to thiopurine treatment might be improved by the addition of allopurinol, together with a reduced thiopurine dose and close hematological monitoring.