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Omapatrilat, the most clinically advanced member of a new class of cardiovascular agents, vasopeptidase inhibitors, is under development at Bristol-Myers Squibb Pharmaceutical Research Institute for the treatment of hypertension and heart failure. An electrospray LC/MS/ MS method has been developed and 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 achieved by semiautomated liquid--liquid extraction, where a robotic liquid handler performed the liquid-transferring steps. The mass spectrometer was operated 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.

The decomposition of both [Alpha]- and [Beta]-anomers of ifetroban 1-O-acyl glucuronide in an aqueous medium was studied at ambient temperature (23 [degrees] C). An HPLC/MS technique was used to investigate the decomposition of these anomers via hydrolysis and acyl migration over a pH range of 1.0-13.0. It was found that while no acyl migration occurred at pH [less than or equal to] 4.0, hydrolysis occurred at both acidic and basic pH. The hydrolysis rate was the slowest within the pH range of 3.0-4.0. Outside this range, the rate of hydrolysis increased as the pH was increased or decreased. The acyl migration at pH 5.0 was very slow, but the rate increased as the pH was increased. First-order rate constants (in [h.sup.-1]), as a function of pH, were estimated according to a simplified scheme for both hydrolysis and acyl migration processes. Methanolysis of the [Beta]-anomer was studied in 80% or 100% methanol in water and also in 20% methanol in aqueous buffer solutions with apparent pH values of 3.0, 6.0 and 9.0. A systematic study of varying the pH and ionic strength of the HPLC mobile phase showed that both parameters significantly affected the resolution and retention times of the positional isomers and anomers. The HPLC method developed was capable of separating all the positional isomeric glucuronides and their anomers.