Influence of xanthine oxidase on thiopurine metabolism in Crohn’s disease

• Published in: Alimentary pharmacology & therapeutics Vol. 28; no. 6; pp. 749 - 757
• Main Authors: ANSARI, A., ASLAM, Z., DE SICA, A., SMITH, M., GILSHENAN, K., FAIRBANKS, L., MARINAKI, A., SANDERSON, J., DULEY, J.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 15-09-2008; Blackwell
• Subjects: Adult; Biological and medical sciences; Biological Availability; Case-Control Studies; Crohn Disease - drug therapy; Crohn Disease - enzymology; Crohn Disease - pathology; Digestive system; Female; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Immunosuppressive Agents - metabolism; Intestine, Small - enzymology; Medical sciences; Mercaptopurine - analogs & derivatives; Mercaptopurine - metabolism; Methyltransferases - genetics; Methyltransferases - metabolism; Other diseases. Semiology; Pharmacology. Drug treatments; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Uric Acid - analogs & derivatives; Uric Acid - urine; Xanthine Oxidase - metabolism; Crohn disease; Enzyme; Thiopurine derivatives; Digestive diseases; Intestinal disease; Xanthine oxidase; Oxidoreductases; Pharmacokinetics; Metabolism; Inflammatory disease
• ISSN: 0269-2813; 1365-2036
• DOI: 10.1111/j.1365-2036.2008.03768.x

Summary
Background  The thiopurines, azathioprine (AZA) and mercaptopurine are extensively used in Crohn’s disease (CD). Thiopurine bioactivation can be diverted by either thiopurine methyltransferase (TPMT), or by xanthine oxidase/dehydrogenase (XOD) which forms 6‐thiouric acid (6TU).
Aim  To investigate whether chronic inflammation could influence small intestinal XOD activity using urinary excretion of 6TU as a surrogate marker of XOD activity.
Methods  6‐Thiouric acid excretion was compared between 32 CD patients and nine dermatology patients (control group), on AZA. Six CD patients were interesting: five with low TPMT activity (one deficient, four intermediate), and one receiving AZA/allopurinol co‐therapy.
Results  There was no statistical difference in 6TU excretion between the CD and control group. CD location, severity or surgery did not affect excretion. The TPMT‐deficient patient excreted 89% of daily AZA dose as 6TU, but excretion by TPMT carriers was essentially normal. Concurrent 5‐aminosalicylic acid therapy increased 6TU excretion significantly (median 32.9%), consistent with inhibiting TPMT. 6TU was undetectable in the patient on AZA/allopurinol co‐therapy.
Conclusions  The results refuted our hypothesis, but fitted a model where most of an oral thiopurine dose effectively escapes first‐pass metabolism by gut XOD, but is heavily catabolized by TPMT. Bioavailability of thiopurines may be competitively inhibited by dietary purines.