TITLE

XANTHINE OXIDASE/DEHYDROGENASE ACTIVITY IN IBD PATIENTS RECEIVING AZATHIOPRINE

AUTHOR(S)
Ansari, A.; De Sica, A.; Duley, J.A.; Shobowale-Bakre, E.M.; Fairbanks, L.; Marinaki, A.; Aslam, M.; Hirst, J.; Smith, C.; Sanderson, J.D.
PUB. DATE
April 2003
SOURCE
Gut;Apr2003 Supplement 1, Vol. 52, pA65
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Catabolism of azathioprine (AZA) occurs via two main pathways: methylation by thiopurine methyltransferase (TPMT) and oxidation by xanthine oxidase/dehydrogenase (XOD). TPMT activity is genetically polymorphic, while XOD deficiency (xanthinuria) is a rare disorder. However, XOD is present in intestinal mucosa and might therefore vary in patients with inflammatory bowel disease (IBD) resulting in altered AZA metabolism, adverse effects and efficacy. We measured 6-thiouric acid (6TU, end-product of XOD oxidation) in 24-hour urines from 31 IBD (27 CD, 4 UC) patients receiving AZA for more than 2 weeks. As non-IBD controls, 9 patients receiving AZA for eczema or bullous pemphigoid were also studied. Results: The overall mean oxidation of AZA to 6TU was 11% (95%C1:3.1-26.6) of the dose. In 16 IBD patients not on 5-ASA (which inhibits TPMT in vitro) mean 6-TU excretion did not differ significantly from dermatology controls (9.4% (3.3-16.7) v 8.6% (3.1-15)) For the 15 IBD patients receiving 5ASA drugs, the mean 6TU excretion was (14.2%; 6.326.6%) significantly higher than the IBD patients not on 5ASA or in dermatology controls (p<0.05, TukeyKramer test). There was no association between AZA oxidation and IBD disease location or severity of disease (CDAI). Oxidation was not raised in 4 of the IBD patients who had intermediate TPMT deficiency. In contrast, an additional IBD patient with zero TPMT, on Iow dose AZA, excreted 90% of the dose as 6TU. As expected, there was a mild association between 6TU excreted on a creatinine basis with AZA dose (mg/kg). Interestingly, the study also revealed several noncompliers, who were excluded from the study. Conclusions: Only about 10% of an AZA dose is oxidised, presumably via XOD: most of the drug is methylated. AZA diversion into oxidation is increased significantly by 5-ASA drugs, but not affected by gut inflammation.
ACCESSION #
9747729

 

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