PMID- 21323897
OWN - NLM
STAT- MEDLINE
DCOM- 20111006
LR  - 20220330
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 163
IP  - 4
DP  - 2011 Jun
TI  - Biotransformation of 6-thioguanine in inflammatory bowel disease patients: a 
      comparison of oral and intravenous administration of 6-thioguanine.
PG  - 722-31
LID - 10.1111/j.1476-5381.2011.01265.x [doi]
AB  - BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY 
      RESULTS: The median AUC per mg 6-TG was 1068 (p.o.) and 7184 (i.v.) pmol.h (8 x 
      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 AND IMPLICATIONS: 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.
CI  - (c) 2011 The Authors. British Journal of Pharmacology (c) 2011 The British 
      Pharmacological Society.
FAU - Jharap, B
AU  - Jharap B
AD  - Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, the 
      Netherlands. b.jharap@vumc.nl
FAU - de Boer, Nkh
AU  - de Boer N
FAU - Vos, Rm
AU  - Vos R
FAU - Smid, K
AU  - Smid K
FAU - Zwiers, A
AU  - Zwiers A
FAU - Peters, Gj
AU  - Peters G
FAU - Mulder, Cjj
AU  - Mulder C
FAU - Wilhelm, Aj
AU  - Wilhelm A
FAU - van Bodegraven, Aa
AU  - van Bodegraven A
LA  - eng
PT  - Journal Article
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Guanine Nucleotides)
RN  - 0 (Thionucleotides)
RN  - 15867-02-4 (6-thioguanylic acid)
RN  - EC 1.17.3.2 (Xanthine Oxidase)
RN  - EC 2.1.1.- (Methyltransferases)
RN  - EC 2.1.1.67 (thiopurine methyltransferase)
RN  - EC 2.4.2.8 (Hypoxanthine Phosphoribosyltransferase)
RN  - FTK8U1GZNX (Thioguanine)
SB  - IM
MH  - Administration, Oral
MH  - Adult
MH  - Female
MH  - Guanine Nucleotides/blood/metabolism
MH  - Humans
MH  - Hypoxanthine Phosphoribosyltransferase/metabolism
MH  - Inflammatory Bowel Diseases/blood/*drug therapy/*metabolism
MH  - Infusions, Intravenous
MH  - Male
MH  - Methyltransferases/metabolism
MH  - Middle Aged
MH  - Prospective Studies
MH  - Thioguanine/*pharmacokinetics/pharmacology
MH  - Thionucleotides/blood/metabolism
MH  - Xanthine Oxidase/metabolism
MH  - Young Adult
PMC - PMC3111675
EDAT- 2011/02/18 06:00
MHDA- 2011/10/07 06:00
PMCR- 2012/06/01
CRDT- 2011/02/18 06:00
PHST- 2011/02/18 06:00 [entrez]
PHST- 2011/02/18 06:00 [pubmed]
PHST- 2011/10/07 06:00 [medline]
PHST- 2012/06/01 00:00 [pmc-release]
AID - 10.1111/j.1476-5381.2011.01265.x [doi]
PST - ppublish
SO  - Br J Pharmacol. 2011 Jun;163(4):722-31. doi: 10.1111/j.1476-5381.2011.01265.x.