The effect of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes: Results from a prospective pharmacological study

Abstract

IntroductionThiopurine therapy is often discontinued in inflammatory bowel disease (IBD) patients. The xanthine oxidase (XO) inhibitor allopurinol has previously shown to enhance thiopurine efficacy and to prevent adverse reactions, the mechanism of this beneficial interaction is not completely clarified. The aim of this study is to observe possible effects of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes. MethodsA prospective study of IBD patients failing thiopurine therapy due to a skewed thiopurine metabolism was performed. Patients were treated with allopurinol and azathioprine or mercaptopurine. Xanthine oxidase, hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and thiopurine S-methyl transferase (TPMT) activities, and thiopurine metabolites concentrations were measured during thiopurine monotherapy, and after 4 and 12weeks of combination therapy. ResultsOf fifteen IBD patients, XO activity decreased from 0.18 (IQR 0.08–0.3) during thiopurine monotherapy to 0.14 (IQR 0.06–0.2) and 0.11 (IQR 0.06–0.2; p=0.008) mU/hour/ml at 4 and 12weeks, respectively. HGPRT activity increased from 150 (IQR 114–176) to 180 (IQR 135–213) and 204nmol/(h×mg protein) (IQR 173–213; p=0.013). TPMT activity seemed not to be affected. 6-Thioguanine nucleotide concentrations increased from 138 (IQR 119–188) to 235 (223–304) and to 265pmol/8×10^8 (IQR 188–344), whereas 6-methyl mercaptopurine ribonucleotides concentrations decreased from 13230 (IQR 7130–17420) to 690 (IQR 378–1325) and 540 (IQR 240–790) pmol/8×10^8 at 4 and 12weeks of combination therapy (both p<0.001). ConclusionAllopurinol and thiopurine combination-therapy seems to increase HGPRT and decrease XO activity in IBD patients, which at least in part may explain the observed changes in thiopurine metabolite concentrations.