Azathioprine Therapy in Multiple Sclerosis: Phosphoribosylated Metabolites and Thiopurine Methyltransferase Activity

Abstract

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 azathio- prine 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 con- ducted 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 in- creased 6-MMP nucleotide levels. These patients are thus at risk for hepatotoxic side effects. Determination of TPMT ac- tivity before azathioprine therapy and monitoring of its metabolites might provide guidance for dose individualization.