RESUMEN
Baclofen is a racemic GABA(B) receptor agonist that has a number of significant pharmacokinetic limitations, including a narrow window of absorption in the upper small intestine and rapid clearance from the blood. Arbaclofen placarbil is a novel transported prodrug of the pharmacologically active R-isomer of baclofen designed to be absorbed throughout the intestine by both passive and active mechanisms via the monocarboxylate type 1 transporter. Arbaclofen placarbil is rapidly converted to R-baclofen in human and animal tissues in vitro. This conversion seems to be primarily catalyzed in human tissues by human carboxylesterase-2, a major carboxylesterase expressed at high levels in various tissues including human intestinal cells. Arbaclofen placarbil was efficiently absorbed and rapidly converted to R-baclofen after oral dosing in rats, dogs, and monkeys. Exposure to R-baclofen was proportional to arbaclofen placarbil dose, whereas exposure to intact prodrug was low. Arbaclofen placarbil demonstrated enhanced colonic absorption, i.e., 5-fold higher R-baclofen exposure in rats and 12-fold higher in monkeys compared with intracolonic administration of R-baclofen. Sustained release formulations of arbaclofen placarbil demonstrated sustained R-baclofen exposure in dogs with bioavailability up to 68%. In clinical use, arbaclofen placarbil may improve the treatment of patients with gastroesophageal reflux disease, spasticity, and numerous other conditions by prolonging exposure and decreasing the fluctuations in plasma levels of R-baclofen.
Asunto(s)
Baclofeno/farmacocinética , Agonistas del GABA/farmacocinética , Profármacos/farmacocinética , Animales , Unión Competitiva/efectos de los fármacos , Butiratos/metabolismo , Carboxilesterasa/metabolismo , Hidrolasas de Éster Carboxílico/metabolismo , Células Cultivadas , Química Farmacéutica , Sistema Enzimático del Citocromo P-450/metabolismo , Humanos , Hidrólisis , Absorción Intestinal , Isobutiratos , Isoenzimas/efectos de los fármacos , Células LLC-PK1 , Masculino , Membranas Artificiales , Oocitos/efectos de los fármacos , Oocitos/metabolismo , Ratas , Ratas Sprague-Dawley , Distribución Tisular , VinoRESUMEN
Further structure-activity relationships of a novel series of fungal efflux pump inhibitors with respect to potentiation of the activity of fluconazole against strains of C. albicans and C. glabrata over-expressing ABC-type efflux pumps are systematically explored. Rat protein binding and pharmacokinetics of selected analogues are reported.
Asunto(s)
Antifúngicos/farmacología , Proteínas de Transporte de Membrana/efectos de los fármacos , Piperazinas/química , Quinazolinonas/farmacología , Suero/química , Animales , Antifúngicos/sangre , Antifúngicos/química , Antifúngicos/farmacocinética , Candida albicans/efectos de los fármacos , Hepatocitos/metabolismo , Masculino , Proteínas de Transporte de Membrana/metabolismo , Estructura Molecular , Piperazina , Quinazolinonas/sangre , Quinazolinonas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Structure-activity relationships of a novel series of fungal efflux pump inhibitors with respect to potentiation of the activity of fluconazole against strains of Candida albicans and Candida glabrata over-expressing ABC-type efflux pumps are systematically explored.
Asunto(s)
Antifúngicos/síntesis química , Candida/efectos de los fármacos , Moduladores del Transporte de Membrana , Proteínas de Transporte de Membrana/antagonistas & inhibidores , Piperazinas/síntesis química , Quinazolinas/síntesis química , Antifúngicos/química , Antifúngicos/farmacología , Candida/enzimología , Candida albicans/efectos de los fármacos , Candida albicans/enzimología , Candida glabrata/efectos de los fármacos , Candida glabrata/enzimología , Farmacorresistencia Fúngica , Sinergismo Farmacológico , Fluconazol/química , Fluconazol/farmacología , Proteínas Fúngicas/antagonistas & inhibidores , Humanos , Pruebas de Sensibilidad Microbiana , Piperazinas/química , Piperazinas/farmacología , Quinazolinas/química , Quinazolinas/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
SAR studies in a series of related 3-(heteroarylthio)cephems determined that a relatively high chemical reactivity of the beta-lactam ring, modulated by electronic effects of substituents at C-3 and C-7, is necessary to achieve high in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA). Such high reactivity results in lowered hydrolytic stability and concomitantly increases susceptibility to beta-lactam ring opening mediated by serum enzymes. Therefore, optimization of anti-MRSA activity versus stability toward serum-mediated degradation required a fine balance of substituent effects. Serum stability studies (measured as percentage of parent drug degraded after 60 min incubation) revealed up to 80-fold difference in degradation rate in a series of closely related (3-heteroarylthio)cephems. Of the compounds evaluated, RWJ-333441 (MC-04,546) possessed the best balance of serum stability (6% degradation after 60 min incubation) and in vitro activity versus MRSA (S. aureus COL MIC=1 microgram/mL). Accordingly, RWJ-333441 displayed excellent in vivo efficacy versus methicillin-susceptible Staphylococcus aureus (MSSA, ED(50)=0.39 mg/kg in mouse sepsis model with S. aureus Smith) and good pharmacokinetic properties in the rat (Cl(total)=0.39 L/h/kg).