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

• Published in: Journal of gastroenterology and hepatology 2011-01, Vol.26 (1), p.49-54
• Main Authors: Gardiner, Sharon J, Gearry, Richard B, Burt, Michael J, Chalmers-Watson, Teresa, Chapman, Bruce A, Ross, Alison G, Stedman, Catherine A M, Huelsen, Alexander, Barclay, Murray L
• Format: Article
• Language: English
• Subjects: 6-mercaptopurine; 6-thioguanine nucleotides; Adult; allopurinol; Allopurinol - adverse effects; Allopurinol - therapeutic use; Anti-Inflammatory Agents - adverse effects; Anti-Inflammatory Agents - pharmacokinetics; Anti-Inflammatory Agents - therapeutic use; azathioprine; Azathioprine - adverse effects; Azathioprine - pharmacokinetics; Azathioprine - therapeutic use; Biological and medical sciences; Biotransformation; Bones, joints and connective tissue. Antiinflammatory agents; Drug Therapy, Combination; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - therapeutic use; Erythrocyte Count; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gastrointestinal Agents - adverse effects; Gastrointestinal Agents - pharmacokinetics; Gastrointestinal Agents - therapeutic use; Guanine Nucleotides - blood; Humans; inflammatory bowel disease; Inflammatory Bowel Diseases - drug therapy; Inflammatory Bowel Diseases - enzymology; Male; Medical sciences; Mercaptopurine - adverse effects; Mercaptopurine - pharmacokinetics; Mercaptopurine - therapeutic use; Middle Aged; New Zealand; Other diseases. Semiology; Pharmacology. Drug treatments; Red-Cell Aplasia, Pure - blood; Red-Cell Aplasia, Pure - chemically induced; Retrospective Studies; Steroids - therapeutic use; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Thionucleotides - blood; Time Factors; Treatment Outcome; Xanthine Oxidase - antagonists & inhibitors; Xanthine Oxidase - metabolism
• ISSN: 0815-9319; 1440-1746
• DOI: 10.1111/j.1440-1746.2010.06489.x

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 × 108 red blood cells (RBC; P = 0.0005), increased 6‐TGN from 162 (125–300) to 332 (135–923) pmol/8 × 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.