Metabolism, disposition, and pharmacokinetics of a potent anticonvulsant, 4-amino-N-(2,6-dimethylphenyl)benzamide (LY201116), in rats.

The metabolism, disposition, and pharmacokinetics of 4-amino-N-(2,6-dimethylphenyl)benzamide (LY201116) have been studied in rats. 14C-LY201116 was well absorbed (approximately 94%) from the gastrointestinal tract following oral administration. Of the dose administered, 64.5% was excreted in the urine and 29% in the bile; with the majority being excreted during the first 24 hr. Peak plasma levels of LY201116 were observed at 0.75 hr, whereas peak plasma concentrations of radioactivity were seen at 2 hr after dosing. Maximum levels of radioactivity were observed at 2 hr in all of the tissues studied. The elimination of radioactivity from the tissues was monophasic with a mean half-life of 3.4 hr. Biotransformation of LY201116 in rats was investigated by quantitating and isolating metabolites from urine and plasma. The major route of metabolism was N-acetylation to form 4-(acetylamino)-N-(2,6-dimethylphenyl)benzamide (ADMP), and subsequent hydroxylation to form 4-(acetylamino)-N-(2-hydroxymethyl-6-methylphenyl)benzamide (HADMP). Two hr after oral dosing with 14C-LY201116, ADMP and HADMP comprised 92% of the total radioactivity in the plasma. The major urinary metabolite, accounting for 63% of the radioactivity in the urine, was HADMP. The elimination of LY201116 from the systemic circulation following iv administration was monophasic, with a terminal t1/2 of 9.4 min. The volume of distribution was 911 ml/kg and the plasma clearance was 66.9 ml/min/kg.