Asunto(s)
Antipsicóticos/administración & dosificación , Benzodiazepinas/administración & dosificación , Lactancia Materna , Adulto , Antipsicóticos/farmacocinética , Benzodiazepinas/farmacocinética , Análisis Químico de la Sangre , Femenino , Humanos , Lactante , Leche Humana/química , Olanzapina , Embarazo , Trastornos Psicóticos/tratamiento farmacológico , Esquizofrenia Paranoide/tratamiento farmacológico , Venas UmbilicalesRESUMEN
A study was conducted to evaluate the pharmacokinetics of CGP 36 742 (3-aminopropyl-n-butyl-phosphinic acid), an orally active gamma-aminobutyric acid B (GABAB) antagonist, in humans. Pharmacokinetic results after a single oral (600 mg) dose included maximum observed concentration (Cmax), 27 mumol/L (95% CI 22.9, 30.8); time to Cmax (tmax), 3 hours (median); half-life (t1/2), 3.6 hours (95% CI 3.24, 3.9); renal clearance (ClR), 125 mL/min (95% CI 114, 136); and absolute bioavailability (Fabs), 0.44 (95% CI 0.33, 0.47). Administration with food decreased the oral systemic availability (Frel) by 30%. The volume of distribution (285 L/kg) was in the order of magnitude of extracellular body water. The absorbed fraction of the compound was excreted completely and unchanged via the kidney, thus renal function would be the limiting factor for excretion. The rate of absorption and amount absorbed did not differ significantly between elderly and young healthy male volunteers, both after single and multiple doses. There was no gender-related difference in pharmacokinetics in healthy elderly volunteers. CGP 36 742 showed an excellent safety profile: there were no clinically relevant changes in cardiovascular variables, body temperature, or blood chemistry. In the placebo-controlled trial, adverse experiences were rare and evenly distributed among participants receiving placebo and the study drug. In addition, a newly developed high-performance liquid chromatography (HPLC) method for measurement of CGP 36 742 concentrations in plasma and urine using fluorescence detection is described.
Asunto(s)
Antagonistas del GABA/farmacocinética , Antagonistas de Receptores de GABA-B , Compuestos Organofosforados/farmacocinética , Administración Oral , Adulto , Envejecimiento/metabolismo , Disponibilidad Biológica , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Antagonistas del GABA/efectos adversos , Humanos , Masculino , Compuestos Organofosforados/efectos adversos , Proyectos Piloto , Factores SexualesRESUMEN
CGP 28,014 is a specific inhibitor of catechol-O-methyltransferase (COMT) in vivo. In humans, the inhibition was assessed by measuring urinary excretion of isoquinolines and with the levodopa test. Following administration of CGP 28,014, urinary excretion of isoquinolines was significantly increased. In rats, CGP 28,014 reduced plasma and striatal concentrations of 3-O-methyldopa (30MD) in a dose-dependent manner. Acute and subchronic administration of CGP 28,014 alone or in combination with the peripherally acting decarboxylase inhibitor benserazide decreased plasma 30MD as an index of COMT inhibition by about 50%. There seems to be a close relationship between the time-course of plasma concentrations of CGP 28,014 and the extent of COMT inhibition assessed by the 30MD/DOPA ratio in plasma.