Objective: In this prospective study, we examined the association between azathioprine dose, levels of its phosphoribosylated metabolites, and the activity of thiopurine methyltransferase in patients with multiple sclerosis (MS). Materials/Methods: Clinical data and blood samples were collected from 27 MS patients who were undergoing azathioprine treatment. In red blood cells, thiopurine methyltransferase (TPMT) activity was determined, and after hydrolysis and cleavage of the phosphoribosyl residue, amounts of 6-thioguanine (6-TG), 6-methyl-thioguanine (6-MTG), 6- methylmercaptopurine (6-MMP) were measured. For clinical evaluation, the expanded disability status score (EDSS) and the multiple sclerosis functional composite (MSFC) were performed. Laboratory and clinical examinations were conducted twice with a 6-month-intervall. Results: Over a broad range of daily azathioprine dose, nearly constant levels of the immunosuppressive-active 6-TG (nucleotides) were found. There was, however, a marked relationship between daily azathioprine dose and 6-MMP nucleotide levels. Especially patients receiving an azathioprine dose of more than 1.5 mg/kg per day in particular presented an exponential increase in 6-MMP levels when TPMT activity was higher than 45 U/g Hb. All the biochemical measurements gave similar results when performed 6 months later. Conclusions: Patients with the combination of a high TPMT-activity and an azathioprine dose of more than 1.5 mg/kg/d exhibit significantly increased 6-MMP nucleotide levels. These patients are thus at risk for hepatotoxic side effects. Determination of TPMT activity before azathioprine therapy and monitoring of its metabolites might provide guidance for dose individualization.
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