Tocainide Conjugation in Humans: Novel Biotransformation Pathway for a Primary Amine

The metabolism of tocainide, an experimental antiarrhythmic drug, was studied in humans. Urinary excretion of unchanged drug was 28-55% in 24 hr after oral dosing. Urine hydrolysis with hydrochloric acid or β-glucuronidase increased tocainide recovery to 55-79%. Saccharo-1,4-lactone inhibited the β-glucuronidase-mediated tocainide recovery increase. Adjustment of urine to pH 13 produced a compound identified as 3-(2,6-xylyl)-5-methylhydantoin. Evidence suggests that it was derived from the same metabolite that formed the additional tocainide after acid or β-glucuronidase treatment. Tocainide carbamoyl O-β-D-glucuronide is the structure proposed for the metabolite. The suggested pathway for its formation involves the addition of carbon dioxide to the amino nitrogen of tocainide followed by uridine diphosphate-glucuronic acid conjugation.