The spleen tyrosine kinase (Syk) inhibitor R406 is orally administered as the prodrug R788. Following administration of R788 (12.5 mg kg(-1), 20 microCi kg(-1 14)C-R788) to intact and bile duct-cannulated cynomolgus monkeys, drug-related radioactivity was rapidly observed in plasma. No R788 was observed in plasma, while R406 was the major radioactive peak observed at all time points. Only low levels of metabolites were observed in plasma. The half-life for plasma radioactivity was 2.0-2.8 h. The majority (68.9%) of drug-related radioactivity was eliminated into bile. No intact R406 was observed in excreta. Biliary and urinary metabolites consisted of glucuronide and sulfate conjugates of the para-O-demethylated metabolite of R406 (R529), and a direct N-glucuronide of R406. The major metabolite in faeces from intact and bile duct-cannulated monkeys was a unique 3,5-benzene diol metabolite of R406. This metabolite was formed following the sequential O-demethylation and para-dehydroxylation of R529 by anaerobic gut bacteria.