METABOLISM OF [14C]GEMOPATRILAT AFTER ORAL ADMINISTRATION TO RATS, DOGS, AND HUMANS

药代动力学 口服 分配量 生物利用度 新陈代谢 尿 化学 最大值 体内 半衰期 代谢物 药理学 二硫苏糖醇 粪便 生物转化 药物代谢 生物化学 生物 生物技术 古生物学
作者
Jill C.M. Wait,Nimish Vaccharajani,James Mitroka,Mohammed Jemal,Sanaullah Khan,Samuel J. Bonacorsi,J. Kent Rinehart,Ramaswamy A. Iyer
出处
期刊:Drug Metabolism and Disposition [American Society for Pharmacology and Experimental Therapeutics]
卷期号:34 (6): 961-970 被引量:7
标识
DOI:10.1124/dmd.105.007500
摘要

This study describes the pharmacokinetic parameters of gemopatrilat, a potent 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 after dose, the mean concentrations of gemopatrilat were less than 1% of the mean Cmax values. The total area under the first-moment time curve extrapolated to infinity [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 liters) 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 dithiothreitol 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.
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