Received for publication September 20, 2005.
Revised March 6, 2006.
Accepted for publication March 7, 2006.

Metabolism and Disposition of [¹⁴C]Gemopatrilat after Oral Administration to Rats, Dogs and Humans

Abstract

This study describes the pharmacokinetic parameters of gemopatrilat, a vasopeptidase inhibitor, in humans and the comparative biotransformation of the compound in rats, dogs and humans after administration of a single oral dose of [¹⁴C]gemopatrilat. Gemopatrilat was rapidly absorbed in humans with an oral bioavailability of 49%. Within 5 h post-dose, the mean concentrations of gemopatrilat were less than 1% of the mean Cmax values. The AUC(INF) value for gemopatrilat was only 2% of the AUC(INF) of radioactivity in plasma. Gemopatrilat showed a large apparent steady-state volume of distribution (2500 L) and a prolonged terminal-phase decline in plasma concentration. These results are consistent with the idea that the free sulfhydryl group of gemopatrilat forms reversible disulfide linkages with plasma and tissue proteins and is thus eliminated from the body at a very slow rate. Approximately half of the drug-related radioactivity in 1 h plasma samples from rat, dog and human was reduced chemically with DTT to gemopatrilat, suggesting that disulfide linkage occurred in all species. In addition, metabolites formed through S-methylation and amide hydrolysis were also detected in rat, dog and human plasma. No gemopatrilat was detected in urine and fecal samples from all three species indicating that the compound is extensively metabolized in vivo. The major metabolites identified in human urine and feces were also present in rat and dog. These data suggest that the metabolism of gemopatrilat in all three species were qualitatively very similar.

Key words: human pharmacokinetics, metabolite identification, methyl transferase, pharmacokinetics, structure elucidation