title: The effect of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes: results from a prospective pharmacological study.
abstract: BACKGROUND
  Thiopurine therapy is often discontinued in inflammatory bowel disease (IBD) patients. The xanthine oxidase (XO) inhibitor allopurinol has previously shown to enhance thiopurine efficacy and to prevent adverse reactions, the mechanism of this beneficial interaction is not completely clarified. The aim of this study is to observe possible effects of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes.
  
  
  METHODS
  A prospective study of IBD patients failing thiopurine therapy due to a skewed thiopurine metabolism was performed. Patients were treated with allopurinol and azathioprine or mercaptopurine. Xanthine oxidase, hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and thiopurine S-methyl transferase (TPMT) activities, and thiopurine metabolites concentrations were measured during thiopurine monotherapy, and after 4 and 12 weeks of combination therapy.
  
  
  RESULTS
  Of fifteen IBD patients, XO activity decreased from 0.18 (IQR 0.08-0.3) during thiopurine monotherapy to 0.14 (IQR 0.06-0.2) and 0.11 (IQR 0.06-0.2; p=0.008) mU/hour/ml at 4 and 12 weeks, respectively. HGPRT activity increased from 150 (IQR 114-176) to 180 (IQR 135-213) and 204 nmol/(h×mg protein) (IQR 173-213; p=0.013). TPMT activity seemed not to be affected. 6-Thioguanine nucleotide concentrations increased from 138 (IQR 119-188) to 235 (223-304) and to 265 pmol/8×10^8 (IQR 188-344), whereas 6-methyl mercaptopurine ribonucleotides concentrations decreased from 13230 (IQR 7130-17420) to 690 (IQR 378-1325) and 540 (IQR 240-790) pmol/8×10^8 at 4 and 12 weeks of combination therapy (both p<0.001).
  
  
  CONCLUSIONS
  Allopurinol and thiopurine combination-therapy seems to increase HGPRT and decrease XO activity in IBD patients, which at least in part may explain the observed changes in thiopurine metabolite concentrations.
authors: Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: ml.seinen@vumc.nl.
authors: M L
authors: ML
authors: Seinen
authors: D P
authors: DP
authors: van Asseldonk
authors: N K H
authors: NK
authors: de Boer
authors: N
authors: N
authors: Losekoot
authors: K
authors: K
authors: Smid
authors: C J J
authors: CJ
authors: Mulder
authors: G
authors: G
authors: Bouma
authors: G J
authors: GJ
authors: Peters
authors: A A
authors: AA
authors: van Bodegraven
mesh_terms: D000328:Adult; D000493:Allopurinol / Q000494:pharmacology*; D001379:Azathioprine / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D004789:Enzyme Activation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006150:Guanine Nucleotides / Q000097:blood; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000201:enzymology*; D008297:Male; D015122:Mercaptopurine / Q000494:pharmacology*; D008780:Methyltransferases / Q000378:metabolism; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D011446:Prospective Studies; D013868:Thioinosine / Q000031:analogs & derivatives / Q000097:blood; D013873:Thionucleotides / Q000097:blood; D014969:Xanthine Oxidase / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D013873:Thionucleotides; C003964:6-thioguanylic acid; D013868:Thioinosine; D000493:Allopurinol; C002344:6-methylthiopurine ribonucleoside-5'-phosphate; D015122:Mercaptopurine; D014969:Xanthine Oxidase; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D007041:Hypoxanthine Phosphoribosyltransferase; D001379:Azathioprine
keywords: Allopurinol; Azathioprine; Hypoxanthine guanine phosphoribosyl transferase; Inflammatory bowel disease; Thiopurine methyl transferase