RESUMEN
Acipimox is an analog of nicotinic acid and is indicated for the treatment of dyslipidemia. It is also believed to improve glucose control by enhancing insulin sensitivity. The purpose of this study was to direct modified release (MR) formulation strategy by comparing the bioavailability of two forms of acipimox (free acid and sodium salt) from the distal small bowel (DSB) and colon with an immediate release formulation. Two parallel groups of healthy volunteers completed an open label, non-randomized, three-way crossover study. The rate and extent of acipimox absorption was highest following administration of the immediate release capsules, and was not influenced by the form of the drug administered. Following administration to the DSB, the relative bioavailability was approximately 52% and 30% for the salt form and free acid form, respectively. Following administration to the colon, the extent of absorption was further reduced. The data indicate that bioavailability from the DSB was limited by the solubility of the drug coupled with an absorption window, whilst absorption from the colon was limited by permeability. The study provided detailed information to support and guide the formulation strategy for a MR form of acipimox, which may improve the treatment of adult patients with type II diabetes and dyslipidemia.
Asunto(s)
Hipolipemiantes/farmacocinética , Pirazinas/farmacocinética , Adulto , Disponibilidad Biológica , Colon/metabolismo , Estudios Cruzados , Preparaciones de Acción Retardada , Femenino , Humanos , Hipolipemiantes/administración & dosificación , Hipolipemiantes/química , Intestino Delgado/metabolismo , Masculino , Persona de Mediana Edad , Permeabilidad , Pirazinas/administración & dosificación , Pirazinas/química , Sales (Química) , Solubilidad , Adulto JovenRESUMEN
The metabolic profile of niacin is influenced by the rate of niacin administration. This study characterizes the effect of administration rate on the pharmacokinetics of niacin and its metabolites. Twelve healthy males were enrolled in an open-label, dose-rate escalation study and received 2000 mg niacin at 3 different dosing rates. Plasma was analyzed for niacin, nicotinuric acid, nicotinamide, and nicotinamide-N-oxide. Urine was analyzed for niacin and the metabolites nicotinuric acid, nicotinamide, nicotinamide-N-oxide, N-methylnicotinamide, and N-methyl-2-pyridone-5-carboxamide. C(max) and AUC(0-t) for niacin and nicotinuric acid increased with an increase in dosing rate. The changes observed in plasma nicotinamide and nicotinamide-N-oxide parameters, however, did not correlate to dosing rate. The total amount of niacin and metabolites excreted in urine was comparable for all 3 treatments. However, with the increase in dosing rate, urine recovery of niacin and nicotinuric acid showed a significant increase, whereas N-methyl-2-pyridone-5-carboxamide and N-methylnicotinamide showed a significant decrease.