Excretion and metabolism of lorcainide in rats, dogs and man.

Abstract

After p.o. or i.v. administration of 3H-lorcainide, excretion of the radioactivity was almost complete within four days. In rats and dogs, about 35% of the dose was excreted in the urine and about 60% in the faeces. However, in humans, 62% was excreted in the urine and 35% in the faeces. In rats, about 70% of the orally administered radioactivity was excreted in the bile within 24 hours. Enterohepatic circulation was proven by "donor-acceptor" coupling in rats. Lorcainide was extensively metabolized. Urinary and faecal metabolites were isolated by extraction and high pressure liquid chromatography (HPLC), and characterized by chromatographic comparison with reference compounds, by mass spectrometry, and NMR. The mass balance for unchanged lorcainide and its major metabolites (determined by radio-HPLC) was very similar in the urine and faeces. Only minor quantitative differences were observed between intravenously and orally dosed animals, and between male and female rats. Major biotransformation pathways in the three species were: hydroxylation, O-methylation and glucuronidation. 4-Hydroxy-3-methoxy-lorcainide was the main metabolite. alpha-Oxidation resulting in alpha, 4-dihydroxy-3-methoxy-lorcainide, was observed in dogs only. Minor pathways were: oxidative N-dealkylation and amide hydrolysis. A remarkable 5-hydroxy-3,4-dimethoxy-metabolite was identified unambiguously in the three species.