RESUMEN
The discovery of a potent intracellular inhibitor of human neutrophil elastase which is orally active and has a long duration of action is described. The pharmacodynamic and pharmacokinetic properties of a trans-lactam development candidate, GW311616A, are described.
Asunto(s)
Lactamas/farmacología , Lactamas/farmacocinética , Piperidinas/química , Piperidinas/farmacología , Serpinas/química , Serpinas/farmacología , Administración Oral , Animales , Bacterias/efectos de los fármacos , Infecciones Bacterianas/tratamiento farmacológico , Disponibilidad Biológica , Cricetinae , Cristalización , Perros , Estabilidad de Medicamentos , Elastasa de Leucocito/antagonistas & inhibidores , Elastasa de Leucocito/metabolismo , Tasa de Depuración Metabólica/fisiología , Elastasa Pancreática/química , Piperidinas/farmacocinética , Ratas , Serina Endopeptidasas/efectos de los fármacos , Serina Endopeptidasas/metabolismo , Serpinas/farmacocinéticaRESUMEN
Described are the acylation binding of trans-lactam 1 to porcine pancreatic elastase, the selection of the SO2Me activating group for the lactam N which also confers metabolic stability in hamster liver microsomes, the introduction of aqueous solubility through the piperidine salt 9, the in vivo oral activity of 9 and its bioavailability, and the introduction of 9 as an intracellular neutrophil elastase inhibitor.
Asunto(s)
Lactamas/farmacocinética , Elastasa de Leucocito/antagonistas & inhibidores , Neutrófilos/efectos de los fármacos , Acilación , Administración Oral , Animales , Sitios de Unión , Cricetinae , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Lactamas/química , Lactamas/farmacología , Modelos Moleculares , Neutrófilos/enzimología , Páncreas/enzimología , Unión Proteica , Pirrolidinas/química , Pirrolidinas/farmacocinética , Pirrolidinas/farmacología , Solubilidad , Relación Estructura-Actividad , PorcinosRESUMEN
The clinical development of salmeterol xinafoate, the 1-hydroxy-2-naphthoic acid salt of salmeterol, a potent long acting beta 2 agonist bronchodilator, has required the development of a method for the determination of 1-hydroxy-2-naphthoic acid (HNA), in human plasma. A sensitive, accurate and precise method was, therefore, required to enable the pharmacokinetic profile to be established. HNA was determined in human plasma using a semi-automated procedure with solid-phase extraction using an automated analytical sample processor (AASP) and high-performance liquid chromatography (HPLC) with fluorescence detection. The method was sensitive to 10 ng ml-1. The method is specific for HNA with respect to endogenous plasma components and has been shown to be robust, accurate and precise. Over four independent assay runs, the relative standard deviations (RSD) of the quality control samples (QC) were 1.6, 2.4 and 5.5% at 180, 100 and 40 ng ml-1, respectively. A pharmacokinetic profile of HNA in man has been established from a single dose kinetic study in healthy volunteers following an oral dose of 500 micrograms salmeterol xinafoate, equivalent to 225 micrograms HNA. Maximum plasma concentrations attained at 1 h after dosing ranged between 35.3 and 66.8 ng ml-1 and were within the calibration range of the assay.
Asunto(s)
Agonistas Adrenérgicos beta/administración & dosificación , Albuterol/análogos & derivados , Naftoles/sangre , Administración Oral , Albuterol/administración & dosificación , Calibración , Cromatografía Líquida de Alta Presión , Humanos , Masculino , Naftoles/farmacocinética , Xinafoato de Salmeterol , Espectrometría de FluorescenciaRESUMEN
An improved high-performance liquid chromatographic (HPLC) assay has been developed for the analysis of labetalol in human plasma. The method is based on the combined use of an automated sample processor, reversed-phase analysis on a microparticulate polymer-based HPLC column and fluorescence detection. The pH stability of the polymeric column packing material allowed the use of a mobile phase adjusted to pH 9.5, which was optimal for the fluorescence of labetalol. Assay validation was undertaken over the labetalol concentration range 2-100 ng/ml. Calibration curves were essentially linear, and the mean coefficient of variation was 5.3%. The assay has been used for the analysis of clinical samples in support of pharmacokinetic studies.