LC/MS/MS determination of omapatrilat, a sulfhydryl-containing vasopeptidase inhibitor, and its sulfhydryl- and thioether-containing metabolites in human plasma

Omapatrilat, the most clinically advanced member of a new class of cardiova scular agents, vasopeptidase inhibitors, is under development at Bristol-My ers Squibb Pharmaceutical Research Institute for the treatment of hypertens ion and heart failure. An electrospray LC/MS/MS method has been developed a nd validated for the simultaneous determination of omapatrilat and its four metabolites in human plasma. Since omapatrilat and two of the metabolites are sulfhydryl-containing compounds, methyl acrylate was used to stabilize these compounds in human blood and plasma samples. Methyl acrylate reacted instantly with the sulfhydryl group to form a derivative that was stable in blood and plasma. Extraction of the analytes from plasma samples was achie ved by semiautomated liquid-liquid extraction, where a robotic liquid handl er performed the liquid-transferring steps. The mass spectrometer Was opera ted in the negative ion selected-reaction-monitoring mode. The calibration curve ranges were 0.5-250 ng/mL for omapatrilat and one metabolite and 2.0- 250 ng/mL for the other three metabolites.