title: Biotransformation of 6-thioguanine in inflammatory bowel disease patients: a comparison of oral and intravenous administration of 6-thioguanine.
abstract: OBJECTIVE
  Although 6-mercaptopurine and azathioprine are effective treatments in inflammatory bowel disease (IBD), many patients discontinue treatment because of side effects. 6-Thioguanine (6-TG) may be an alternative rescue therapy in these intolerant patients but the pharmacokinetics of 6-TG are not fully described. Here we have measured the pharmacokinetics of the biotransformation of 6-TG into the pharmacologically active metabolites, 6-thioguanine nucleotides (6-TGN), in IBD patients.
  
  
  METHODS
  In 12 patients with IBD, levels of 6-TGN and activities of thiopurine S-methyltransferase, xanthine oxidase and hypoxanthine guanine-phosphoribosyl-transferase were measured in a two-stage (i.v. and p.o. administration of 0.3 mg·kg(-1) 6-TG), prospective study. Median exposure of 6-TGN in red blood cells (RBC) was expressed as the ratio of the area under the curve (AUC) per mg 6-TG after i.v. dosing and that after p.o. dosing.
  
  
  RESULTS
  The median AUC per mg 6-TG was 1068 (p.o.) and 7184 (i.v.) pmol·h (8 × 10(8) RBC)(-1) . Median exposure of 6-TGN in RBC was 15% (9-28). Hypoxanthine guanine-phosphoribosyl-transferase activity correlated with peak 6-TGN and with AUC per mg (r= 0.7, P= 0.02 and r= 0.6, P= 0.03 respectively). Thiopurine S-methyltransferase activity was inversely related to AUC per mg (r=-0.8, P= 0.001), whereas that of xanthine oxidase was correlated with a lower peak 6-TGN (r=-0.7, P= 0.02).
  
  
  CONCLUSIONS
  The great variability of the AUC per mg for 6-TG observed after p.o. and i.v. administration of 6-TG, was partly explained by variability in activities of metabolizing enzymes. Exposure of 6-TGN was low in all patients.
authors.affiliation: Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, the Netherlands. b.jharap@vumc.nl
authors.forename: B
authors.initials: B
authors.lastname: Jharap
authors.forename: Nkh
authors.initials: N
authors.lastname: de Boer
authors.forename: Rm
authors.initials: R
authors.lastname: Vos
authors.forename: K
authors.initials: K
authors.lastname: Smid
authors.forename: A
authors.initials: A
authors.lastname: Zwiers
authors.forename: Gj
authors.initials: G
authors.lastname: Peters
authors.forename: Cjj
authors.initials: C
authors.lastname: Mulder
authors.forename: Aj
authors.initials: A
authors.lastname: Wilhelm
authors.forename: Aa
authors.initials: A
authors.lastname: van Bodegraven
mesh_terms: D000284:Administration, Oral; D000328:Adult; D005260:Female; D006150:Guanine Nucleotides / Q000097:blood / Q000378:metabolism; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D007262:Infusions, Intravenous; D008297:Male; D008780:Methyltransferases / Q000378:metabolism; D008875:Middle Aged; D011446:Prospective Studies; D013866:Thioguanine / Q000493:pharmacokinetics* / Q000494:pharmacology; D013873:Thionucleotides / Q000097:blood / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism; D055815:Young Adult
chemical_list: D006150:Guanine Nucleotides; D013873:Thionucleotides; C003964:6-thioguanylic acid; D014969:Xanthine Oxidase; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D007041:Hypoxanthine Phosphoribosyltransferase; D013866:Thioguanine