title: Febuxostat as a novel option to optimize thiopurines' metabolism in patients with inadequate metabolite levels.
abstract: OBJECTIVE
  To report the use of febuxostat in order to potentiate thiopurines' metabolism in a patient on azathioprine (AZA) therapy with low metabolite 6-thioguanine nucleotides (6-TGN) levels and elevated metabolite 6-methylmercaptopurine (6-MMP) levels.
  
  
  METHODS
  A 44-year-old woman with a history of anti-signal recognition particle necrotizing myopathy was treated with AZA-allopurinol combination therapy. When she developed an atypical drug-induced hypersensitivity syndrome, allopurinol was replaced by the new xanthine oxidase (XO) inhibitor febuxostat, at a daily dose of 40 mg. Febuxostat-AZA combination was successful with 6-TGN reaching therapeutic levels while 6-MMP levels remained low. After 5 months, she developed similar manifestations that she had presented on AZA-allopurinol combination. Febuxostat and AZA were then stopped.
  
  
  CONCLUSIONS
  AZA and 6-MP are both inactive pro-drugs that undergo a complex metabolic transformation leading to active 6-TGN and potentially hepatotoxic 6-MMP. Some patients with unfavorable thiopurine metabolism might benefit from addition of XO inhibitor allopurinol in order to potentiate 6-TGN and reduce 6-MMP levels. It is likely that febuxostat, via its XO inhibition, would exhibit the same effect on thiopurines' metabolism.
  
  
  CONCLUSIONS
  It has been shown that low dose of febuxostat was able to prevent hypermethylation and to potentiate 6-TGN levels in an AZA-treated patient. Thus, febuxostat could be useful in optimizing thiopurines' metabolism, but more data are needed before this practice can be recommended. The mechanisms by which febuxostat optimizes thiopurines' metabolism remain to be confirmed. Also, the optimal dose of febuxostat for this use remains to be determined.
authors: Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada.
authors: Maxime
authors: M
authors: Doré
authors: Anne Julie
authors: AJ
authors: Frenette
authors: Anne-Marie
authors: AM
authors: Mansour
authors: Yves
authors: Y
authors: Troyanov
authors: Josiane
authors: J
authors: Bégin
mesh_terms: D000328:Adult; D001379:Azathioprine / Q000008:administration & dosage*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D000069465:Febuxostat; D005260:Female; D006150:Guanine Nucleotides / Q000097:blood*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D015122:Mercaptopurine / Q000031:analogs & derivatives* / Q000097:blood; D009135:Muscular Diseases / Q000188:drug therapy*; D013844:Thiazoles / Q000008:administration & dosage*; D013873:Thionucleotides / Q000097:blood*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
chemical_list: D004791:Enzyme Inhibitors; D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D013844:Thiazoles; D013873:Thionucleotides; D000069465:Febuxostat; C003964:6-thioguanylic acid; C010240:6-methylthiopurine; D015122:Mercaptopurine; D014969:Xanthine Oxidase; D001379:Azathioprine
keywords: 6-mercaptopurine; allopurinol; azathioprine; drug-induced hypersensitivity syndrome; febuxostat; hypermethylation; thiopurine S-methyltransferase; thiopurines; xanthine oxidase