Mesalazine Mercaptopurine

Thiopurines are metabolized by thiopurine methyltransferase, whose activity is controlled by a common genetic polymorphism in the short arm of chromosome 6. Patients with low or intermediate activity who take azathioprine or 6-mercaptopurine are at risk of myelosup-pression caused by excess accumulation of the active thiopurine metabolite 6-thioguanine nucleotide. Benzoic acid derivatives, such as mesalazine and its precursors, and prodrugs (sulfasalazine, olsalazine, and balsalazide) inhibit thiopurine methyltransferase activity in vitro. This action could explain the increase in whole blood concentrations of 6-thioguanine nucleotide, leading to leukopenia. 

A 50-year-old woman with Crohn s disease and active disease throughout the colon was given prednisolone, mesalazine, and azathioprine 50 mg/day. After 3 weeks, the dose of azathioprine was increased to 100 mg/day, but she developed nausea, severe diarrhea, and abdominal tenderness. The symptoms subsided after azathioprine was withdrawn. She was then given mercaptopurine, without significant adverse effects. 

The haematological toxicity of azathioprine and mercaptopurine may be increased by mesalazine, olsalazine or sulfasalazine. Bal-salazide may be less likely to interact but this requires confirmation. 

Drug-drug interactions Azathioprine/6-mercaptopurine The association between mesalazine and the induction of myelotoxicity by thiopurine therapy in patients with inflammatory bowel disease was investigated by using both retrospective and prospective studies. Of the 139 patients included in ffie retrospective observational study, 45 were on azathioprine/6-mercaptopurine plus mesalazine, while 94 were on azatiiioprine/6-mercaptopurine alone. The dose of azathioprine in the retrospective study was 2 mg/kg/day, while ffie dose of 6-mercaptopurine was 1 mg/kg/day. Their myelotoxicity rates were 47% and 16%, respectively. Multivariate regression analysis indicated that concomitant mesalazine was the only risk factor associated with myelotoxicity (odds ratio 3.45,95% confidence interval 1.31-9.04, P = 0.01). The prospective study was performed in 16 patients with active disease, treated with azathioprine (50 mg/ day) for 4 weeks followed by concomitant mesalazine (3 g/day) for additional 4 weeks. After 4 weeks on azathioprine no patient developed myelotoxicity. However, after an additional 4 weeks with concomitant mesalazine, two patients developed myelotoxicity. Overall, it appears that the risk of thiopurine-induced myelotoxicity is markedly increased in patients treated with combined mesalazine and 2 mg/kg/day azathioprine. Azathioprine (50 mg, daily) with concomitant mesalazine might help to maintain efficacy without increasing the risk of myelotoxicity [80 ]. 

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