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P234. The effect of allopurinol on thiopurine metabolite concentrations in patients with inflammatory bowel disease

T.L. Asser1, N.A. Kennedy2, P.A. Bampton2, J.M. Andrews3, D. Elliott4, M.P. Doogue5

1University of South Australia, Adelaide, SA, Australia; 2Dept of Gastroenterology, Flinders Medical Centre and School of Medicine, Flinders University, Adelaide, SA, Australia; 3IBD service, Royal Adelaide Hospital and Dept of Medicine, University of Adelaide, Adelaide, SA, Australia; 4SA Pathology, Adelaide, SA, Australia; 5Dept of Clinical Pharmacology, Flinders Medical Centre and School of Medicine, Flinders University, Adelaide, SA, Australia

Background: Thiopurines are metabolized via several pathways to multiple metabolites, including the active metabolites 6-thioguanine nucleotides (6TGN) and the hepatotoxic 6-methyl-mercaptopurine (6MMP). Some patients (shunters) preferentially produce 6MMP with resultant low [6TGN]. Co-administration of allopurinol increases [6TGN] and decreases [6MMP] and hence is increasingly co-prescribed to patients on azathioprine with high [6MMP] and/or subtherapeutic [6TGN].

Aim: To quantify the effect of allopurinol on thiopurine metabolite concentrations.

Methods: Nineteen inflammatory bowel disease patients co-prescribed allopurinol and a thiopurine were identified from clinical and laboratory records. For all patients [6TGN] and [6MMP] data before and after allopurinol initiation were examined, as were ALT and neutrophil count. Changes in thiopurine metabolite concentrations were analysed using Wilcoxon matched pairs or Fishers exact tests.

Results: Before allopurinol, the mean (±SD) daily azathioprine dose was 174 mg (±32), this was reduced by 2/3 on commencement of allopurinol in most cases, to a mean of 59 mg (±15). Before allopurinol mean [6TGN] and [6MMP] were 206 (±79) and 10541 (±8035) pmol/8×108 erythrocytes respectively. On allopurinol [6TGN] and [6MMP] were 474 (±389) and 295 (±265) pmol/8×108 erythrocytes, representing a dose adjusted 8.2 fold increase in [6TGN] and a corresponding 25.5 fold decrease in [6MMP].

Before allopurinol, 12/19 patients had low [6TGN] (<235 pmol/8×108 erythrocytes) whereas only 3/19 had a low concentration on allopurinol (p = 0.007). Before allopurinol, [6MMP] above the recommended threshold was present in 14/17 subjects and none when on allopurinol (p < 0.001). No patient had ALT above the reference range prior to treatment with allopurinol. With allopurinol the [6TGN] increased above the therapeutic range (>450 pmol/8×108 erythrocytes) in 8/19 patients; however, there was no evidence of resultant myelotoxicity.

Conclusions: The use of allopurinol in shunters to reduce [6MMP] and increase [6TGN] is effective. In patients with 6-TGN in the therapeutic range prior to the administration of allopurinol a reduction in dose greater than two thirds should be considered.

Figure 1. Change in [6TGN] with allopurinol (pmol/8×108 RBC).

Figure 2. Change in [6MMP] with allopurinol (pmol/8×108 RBC).