title: Review article: the benefits of pharmacogenetics for improving thiopurine therapy in inflammatory bowel disease.
abstract: BACKGROUND
  Thiopurines represent an effective and widely prescribed therapy in inflammatory bowel disease (IBD). Concerns about toxicity, mainly resulting from a wide inter-individual variability in thiopurine metabolism, restrict their use. Optimal thiopurine dosing is challenging for preventing adverse drug reactions and improving clinical response.
  
  
  OBJECTIVE
  To review efficacy and toxicity of thiopurines in IBD. To provide pharmacogenetic-based therapeutic recommendations.
  
  
  METHODS
  We conducted a query on PubMed database using 'inflammatory bowel disease', 'thiopurine', 'azathioprine', '6-mercaptopurine', 'TPMT', 'pharmacogenetics', 'TDM', and selected relevant articles, especially clinical studies.
  
  
  RESULTS
  Thiopurine metabolism - key enzyme: thiopurine S-methyltransferase (TPMT) - modulates clinical response, as it results in production of the pharmacologically active and toxic metabolites, the thioguanine nucleotides (6-TGN). Adjusting dosage according to TPMT status and/or metabolite blood levels is recommended for optimising thiopurine therapy (e.g. improving response rate up to 30% or decreasing haematological adverse events of 25%). Other enzymes or transporters of interest, as inosine triphosphatase (ITPase), glutathione S-transferase (GST), xanthine oxidase (XO), aldehyde oxidase (AOX), methylene tetrahydrofolate reductase (MTHFR) and ATP-binding cassette sub-family C member 4 (ABCC4) are reviewed and discussed for clinical relevance.
  
  
  CONCLUSIONS
  Based on the literature data, we provide a therapeutic algorithm for thiopurines therapy with starting dose recommendations depending on TPMT status and thereafter dose adjustments according to five metabolite profiles identified with therapeutic drug monitoring (TDM). This algorithm allows a dosage individualisation to optimise the management of patients under thiopurine. Furthermore, identification of new pharmacogenetic biomarkers is promising for ensuring maximal therapeutic response to thiopurines with a minimisation of the risk for adverse events.
authors: Assistance publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Biochimie, Pharmacogénétique et Oncologie Moléculaire, Paris, France.
authors: L
authors: L
authors: Chouchana
authors: C
authors: C
authors: Narjoz
authors: P
authors: P
authors: Beaune
authors: M-A
authors: MA
authors: Loriot
authors: X
authors: X
authors: Roblin
mesh_terms: D000465:Algorithms; D001379:Azathioprine / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008780:Methyltransferases / Q000378:metabolism; D010597:Pharmacogenetics; D017410:Practice Guidelines as Topic; D013866:Thioguanine / Q000627:therapeutic use*
chemical_list: D007166:Immunosuppressive Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D013866:Thioguanine; D001379:Azathioprine