RESUMEN
The purpose of this study was to investigate the pharmacokinetics and in vitro/in vivo correlation (IVIVC) of huperzine A loaded poly(lactic-co-glycolic acid) (PLGA) microspheres in dogs. Several huperzine A loaded PLGA microspheres were prepared by an O/W method and three of them (single dose) were injected intramuscularly (i.m.) or subcutaneously (s.c.) to five beagle dogs, respectively. With the increase of the molecular weight of PLGA and the particle size of microspheres, the in vitro and in vivo release periods of huperzine A were prolonged. After s.c. injection, the release of huperzine A from microspheres was faster than that after i.m. injection. The IVIVC models of huperzine A loaded PLGA microspheres were established successfully and after i.m. administration the linear relationship between the in vitro and the in vivo releases was better than that after s.c. administration. It was also found when the particle size of the microspheres was smaller; the values of correlation coefficient were higher.
Asunto(s)
Ácido Láctico/química , Microesferas , Ácido Poliglicólico/química , Polímeros/química , Sesquiterpenos/farmacocinética , Alcaloides , Animales , Área Bajo la Curva , Disponibilidad Biológica , Inhibidores de la Colinesterasa/administración & dosificación , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacocinética , Cromatografía Liquida/métodos , Perros , Composición de Medicamentos/métodos , Femenino , Inyecciones Intramusculares , Inyecciones Subcutáneas , Masculino , Espectrometría de Masas/métodos , Tamaño de la Partícula , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Sesquiterpenos/administración & dosificación , Sesquiterpenos/químicaRESUMEN
AIM: To isolate and identify a glucuronide metabolite of SFZ-47 [3H-1,2-dihydro-2-(4-methyl-phenylamino)methyl-1-pyrrolizinone], which is difficult to synthesize because it undergoes hydrolysis and intramolecular acyl migration at physiological pH, in rabbit urine. METHODS: Two rabbits were ig 200 mg doses of SFZ-47. Urine was collected for 24 h, adjusted to pH 4.0 with acetic acid and lyophilized. The residues were reconstituted in 25 mL methanol and centrifuged at 5,000 r.min-1 for 10 min. The supernatant was filtered (0.45 micron) and then isolated with semi-preparative reversed phase HPLC. The eluent collected from individual peaks was evaporated by rotary evaporation and freeze-drying. Compounds were then identified with electrospray ion trap mass spectrometry and 1HNMR spectroscopy. RESULTS: The 1HNMR and ESI-MSn results indicate that the metabolite is the 1-O-acyl beta-D-glucuronide conjugate of 4-(3H-1,2-dihydro-1-pyrrolizinone-2-methylamino) benzoic acid. CONCLUSION: This method was shown to be rapid and simple and gave excellent resolution from endogenous constituents in urine, and it is suitable for preparation of the glucuronide metabolites of SFZ-47 and its analogues.