The role of xanthine oxidase in thiopurine metabolism: a case report.
Azathioprine (AZA) is widely used in the treatment of autoimmune inflammatory diseases. AZA is normally rapidly and almost completely converted to 6-mercaptopurine (6-MP) in the liver, which is further metabolized into a variety of pharmacologic active thiopurine metabolites. 6-MP is catabolized by xanthine oxidase (XO) to the inactive metabolite 6-thiouric acid. The authors report the case of a woman with chronic autoimmune pancreatitis unable to form active thiopurine metabolites. The 55-year-old woman presented with weight loss, progressive elevation of liver transaminases, and serum amylase. She was treated with prednisolone 30 mg/day (1 mg/kg) and AZA was increased to 75 mg/day (2.5 mg/kg); this was later increased to 150 mg/day (5 mg/kg). Despite good patient compliance, the active metabolites of AZA, 6-thioguanine nucleotides (6-TGN), and 6-methylmercaptopurine ribonucleotides (6-MMPR) could not be detected in the erythrocytes (RBC). Subsequently, AZA was switched to high-dose 6-MP (2.5 mg/kg) and the XO inhibitor allopurinol was added. After 1 week, this combination led to a high 6-TGN level of 616 pmol/8 x 10(8) RBC and a 6-MMPR level of 1319 pmol/8 x 10(8) RBC. Three weeks after starting treatment, 6-TGN and 6-MMPR even reached toxic levels (1163 pmol/8 x 10(8) RBC and 10015 pmol/8 x 10(8) RBC, respectively) so that 6-MP treatment was discontinued. To elucidate this finding, 6-MP (1.7 mg/kg) was prescribed for 3 days without allopurinol. The woman was not able to form active thiopurine metabolites. According to the authors, this is the first report of a patient unable to form detectable active thiopurine metabolites on AZA and 6-MP therapy despite good patient compliance. High XO activity led to an inability to form detectable levels of active thiopurine metabolites 6-TGN and 6-MMPR. This finding emphasizes the important role of XO in the biotransformation of thiopurines.
Wong
Dennis R
DR
Department of Clinical Pharmacy, Orbis Medical Center, Maasland Hospital, Sittard, The Netherlands. d.wong@orbisconcern.nl
Derijks
Luc J J
LJ
den Dulk
Meyno O
MO
Gemmeke
Edy H K M
EH
Hooymans
Piet M
PM
D001379:Azathioprine / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D015122:Mercaptopurine / Q000378:metabolism; D008875:Middle Aged; D050500:Pancreatitis, Chronic / Q000188:drug therapy; D014969:Xanthine Oxidase / Q000378:metabolism*
D015122:Mercaptopurine; D014969:Xanthine Oxidase; D001379:Azathioprine