Association of Azathioprine Metabolite Levels and Adverse Reactions in Japanese Patients with Inflammatory Bowel Disease

Azathioprine (AZA) is administered for treatment of inflammatory bowel disease (IBD), though it frequently induces severe adverse reactions (ARs). AZA is converted to the active metabolite 6-thioguanine nucleotide (6-TGN) through 6-mercaptoprine (6-MP) and 6-thioinosine phosphate (6-TIP) by various metabolic enzymes, with 6-MP and 6TIP excreted after methylation. Prior studies have found that a 6-TGN level above the threshold of 450 pmol/8x10 red blood cells is associated with increased risk of myelotoxicity. In the present study, we investigated the association of blood concentrations of AZA metabolites with ARs. Blood samples were collected over a period of 52 weeks from 49 Japanese IBD patients prescribed with AZA. After removing protein, we measured the levels of dephosphorylated AZA metabolites using liquid chromatography and mass spectrometry in tandem, then categorized the metabolites into 6-MPs, 6-methylmercaptoprines (6-MMPs), and 6-TGNs, and compared their levels between patients with and without ARs. Statistical analysis was performed using a MannWhitney U-test. ARs developed in 14 of the 49 patients (28.6%). The average concentrations of 6-MMPs and the 6-MMPs/6-TGNs ratio in patients without were significantly greater as compared to those with ARs (P<0.05). In addition, leukopenia was detected in 10 (20.4%) of the patients with ARs and 6-TGNs levels were significantly higher in leukopenia patients (P<0.01). Accordingly, we consider that monitoring is useful for predicting AR occurrence.