title: Allopurinol might improve response to azathioprine and 6-mercaptopurine by correcting an unfavorable metabolite ratio.
abstract: OBJECTIVE
  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/8×10(8) red blood cells (RBC; P=0.0005), increased 6-TGN from 162 (125-300) to 332 (135-923) pmol/8×10(8) 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.
authors.affiliation: Department of Medicine, University of Otago, Christchurch, New Zealand.
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Gardiner
authors.forename: Richard B
authors.initials: RB
authors.lastname: Gearry
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Burt
authors.forename: Teresa
authors.initials: T
authors.lastname: Chalmers-Watson
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Chapman
authors.forename: Alison G
authors.initials: AG
authors.lastname: Ross
authors.forename: Catherine A M
authors.initials: CA
authors.lastname: Stedman
authors.forename: Alexander
authors.initials: A
authors.lastname: Huelsen
authors.forename: Murray L
authors.initials: ML
authors.lastname: Barclay
mesh_terms: D000328:Adult; D000493:Allopurinol / Q000009:adverse effects / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001379:Azathioprine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001711:Biotransformation; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D004906:Erythrocyte Count; D005260:Female; D005765:Gastrointestinal Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006150:Guanine Nucleotides / Q000097:blood; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008875:Middle Aged; D009520:New Zealand; D012010:Red-Cell Aplasia, Pure / Q000097:blood / Q000139:chemically induced; D012189:Retrospective Studies; D013256:Steroids / Q000627:therapeutic use; D013873:Thionucleotides / Q000097:blood; D013997:Time Factors; D016896:Treatment Outcome; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D005765:Gastrointestinal Agents; D006150:Guanine Nucleotides; D013256:Steroids; D013873:Thionucleotides; C003964:6-thioguanylic acid; D000493:Allopurinol; D015122:Mercaptopurine; D014969:Xanthine Oxidase; D001379:Azathioprine