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Abstract: Background and aims: A drug interaction between infliximab and azathioprine has previously been reported in Crohn's disease patients: the concentration of the main active thiopurine metabolites, the 6-thioguanine nucleotides (6-TGN), increased 1–3weeks after the first infliximab infusion by 50% compared to baseline. The aim of this prospective study was to determine the effect of adalimumab on thiopurine metabolism in Crohn's disease patients, evaluated by 6-TGN and 6-methylmercaptopurine ribonucleotides (6-MMPR) concentration measurement. Methods: Crohn's disease patients on azathioprine or mercaptopurine maintenance therapy starting with concomitant adalimumab treatment were included. 6-TGN and 6-MMPR concentrations were determined before initiation of adalimumab and after 2, 4, 6 and 12weeks of combination therapy. The activity of three essential enzymes involving thiopurine metabolism, thiopurine S-methyltransferase (TPMT), hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and inosine-triphosphate pyrophosphatase (ITPase), was evaluated at baseline and week 4. Clinical outcome was evaluated by the Crohn's disease activity index and C-reactive protein concentrations at baseline, week 4 and week 12. Results: Twelve Crohn's disease patients were analyzed. During the follow-up period of 12weeks the median 6-TGN and 6-MMPR concentrations did not significantly change compared to baseline. TPMT, ITPase and HGPRT enzyme activity did not change either after 4weeks. In two patients (17%) myelotoxicity was observed within 2–4weeks, in whom both low therapeutic 6-TGN and 6-MMPR concentrations were found. Conclusions: In this study in Crohn's disease patients no pharmacokinetic interaction was shown between adalimumab and the conventional thiopurines, azathioprine and mercaptopurine. [Copyright &y& Elsevier]

Abstract: In a 23-year-old female with colonic Crohn''s disease 6-mercaptopurine 100mg daily (1.7mg/kg) was added to mesalamine and prednisolone therapy because of ongoing disease activity. One month later she had fever and a pancytopenia. 6-Methylmercaptopurine ribonucleotides levels were extremely elevated (57,000pmol/8×108 red blood cells) and 6-thioguanine nucleotides levels were subtherapeutically (126pmol/8×108 red blood cells). Genotyping showed a wildtype thiopurine S-methyltransferase TPMTH/H (*1/*1) genotype and a wildtype inosine triphosphate pyrophosphatase gene. TPMT and inosine triphosphate pyrophosphatase activity were normal. The pancytopenia recovered spontaneously within a few weeks, parallel with decreasing 6-methylmercaptopurine ribonucleotides levels after interrupting 6-mercaptopurine treatment. Epstein-Barrvirus, Cytomegalovirus and Herpesvirus infections were excluded by serology. This is the first report of pancytopenia due to extremely high 6-methylmercaptopurine ribonucleotides levels. No relation was found with the genotype of TPMT and inosine triphosphate pyrophosphatase enzymes, which play key roles in the thiopurine metabolic pathway. Apparently, 6-methylmercaptopurine ribonucleotides metabolites can cause pancytopenia, as was already known for 6-thioguanine nucleotides. [Copyright &y& Elsevier]

Abstract: The immunosuppressive thiopurines, azathioprine (AZA) and 6-mercaptopurine (6-MP), have proven efficacy in steroid-dependant or refractory inflammatory bowel disease (IBD). In case of TPMT deficiency serious myelosuppression may occur. 6-thioguanine (6-TG), has been suggested in case of AZA and 6-MP resistant or intolerant patients. Our case demonstrates that very low dose 6-TG under close clinical surveillance and frequent therapeutic drug monitoring, may be a rescue drug for IBD-patients with low or without functional TPMT activity. [Copyright &y& Elsevier]