Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine

Abstract

SUMMARYBackground: Many non-responders to azathioprine or mercaptopurine (6-mercaptopurine) have high normal thiopurine methyltransferase activity and preferentially metabolize mercaptopurine to produce 6-methylmercaptopurine instead of the active 6-tioguanine (6-tioguanine) metabolites. Aim: To describe the use of allopurinol in mercaptopurine/azathioprine non-responders to deliberately shunt metabolism of mercaptopurine towards 6-tioguanine. Methods: Fifteen thiopurine non-responders whose metabolites demonstrated preferential metabolism towards 6-methylmercaptopurine are described. Subjects were commenced on allopurinol 100 mg po daily and mercaptopurine/azathioprine was reduced to

Allopurinol safely and effectively optimises thiopurine metabolites in patients with autoimmune hepatitis

“…6 The co-administration of allopurinol alongside low-dose thiopurine redirects the thiopurine metabolism towards 6-TGN formation instead of 6-MMPs. 7,8 This strategy has been successfully applied to a subgroup of inflammatory bowel disease (IBD) patients, where nonresponsiveness to or side effects from thiopurine therapy were attributed to high 6-MMP levels. 9 Here, we report the first clinical experience on efficacy and safety of allopurinol salvage therapy in AIH patients.…”

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

“…Sparrow and colleagues not only showed that upon allopurinol combination therapy 6-TGN concentrations increase, but also that 6-MMPR concentrations decrease. 12 Moreover, 6-MMPR associated liver test abnormalities ameliorated during combination therapy. Recently, combination therapy of allopurinol and low-dose thiopurine in IBD patients was also shown to prevent non-hepatic adverse events that had occurred during standard dosed thiopurine monotherapy.…”

“…3,9,10 The classical XO inhibitor allopurinol, usually prescribed for the treatment of gout, can enhance the efficacy of thiopurine therapy in renal transplant and IBD patients. [11][12][13][14][15][16] The enhanced efficacy is assumed to be due to an increase of 6-TGN concentrations. As severe leukopenia may occur with high 6-TGN concentrations, thiopurine dosages need to be reduced to approximately 25% of their original weight-based dose during combination therapy.…”

Brazilian society of hepatology recommendations for the diagnosis and management of autoimmune diseases of the liver

“…In the presence of histological remisson, with none of minimal portal inflammatory activity disclosed at liver biopsy, treatment withdrawal should be carefully evaluated and discussed with the patient, because relapse rates can be observed in up to 70%-80% of the subjects, requiring reintroduction of higher doses of immunossupression or leading to disease dacompensation in those subjects with cirrhosis and poor liver function. Relapse usually occurs insidiously in the first six months of treatment withdrawal and should be regularly monitored with periodic measurement of AST and ALT (4,41) .It should also be taken into account, the AA profile, since anti-SLA reactivity is associated with higher relapse rates (26) . It is uncertain whether the treatment outcomes after relapse would be worse or better when compared to previous response to therapy (4) .…”