RESUMEN
Pharmacokinetics of compound M-11 (main metabolite of afobazole) after administration via different routes was studied in rats. After oral and intravenous administration, M-11 exhibited weakly pronounced bioconversion with the formation of a few metabolites that could be detected in plasma samples for about 3 hours. The absolute bioavailability of M-11 after oral administration was 68.3%. It was found that M-11 was completely absorbed from gastrointestinal tract of rats and characterized by "the first pass effect", after which approximately 70% of administered dose entered the circulation. The parent substance was determined neither in urine nor in feces.
Asunto(s)
Ansiolíticos/farmacocinética , Bencimidazoles/farmacocinética , Morfolinas/farmacocinética , Animales , Ansiolíticos/administración & dosificación , Ansiolíticos/sangre , Ansiolíticos/orina , Trastornos de Ansiedad/tratamiento farmacológico , Área Bajo la Curva , Bencimidazoles/administración & dosificación , Bencimidazoles/sangre , Bencimidazoles/orina , Disponibilidad Biológica , Biotransformación , Cromatografía Liquida , Heces/química , Tracto Gastrointestinal/fisiología , Semivida , Infusiones Parenterales , Inyecciones Intravenosas , Límite de Detección , Masculino , Morfolinas/administración & dosificación , Morfolinas/sangre , Morfolinas/orina , Ratas , Espectrometría de Masas en TándemRESUMEN
Experiments on conscious male rats have shown that, under conditions of the aconitine-induced arrhythmia model, afobazole and other 2-mercaptobensimidazole derivatives exhibit antiarrhythmic effect, i.e. possess properties of rapid Na+ channel antagonists. The effect of afobazole under these conditions was significantly more pronounced than that of the reference drugs lidocaine and procainamide. The antiarrhythmic (antifibrillatory) effect of afobazole was also detected under the conditions of arrhythmia caused by high doses of calcium chloride. This drug was 1.5 times more effective in its antifibrillatory action than lidocaine, but it was less effective than verapamil. It has been also found that afobazole possesses a wider therapeutic spectrum than the well-known antiarrhythmic drugs of class I and IV (lidocaine, procainamide, ethmosine and verapamil).
Asunto(s)
Antiarrítmicos/farmacología , Arritmias Cardíacas/tratamiento farmacológico , Bencimidazoles/farmacología , Morfolinas/farmacología , Aconitina , Animales , Antiarrítmicos/química , Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/fisiopatología , Bencimidazoles/química , Cloruro de Calcio , Masculino , Morfolinas/química , Ratas , Bloqueadores de los Canales de Sodio/química , Bloqueadores de los Canales de Sodio/farmacología , Relación Estructura-ActividadRESUMEN
Metabolism of afobazole in rats has been studied using mass-spectrometry and HPLC, which revealed 17 products of afobazole biotransformation along with the parent compound. The structures of six afobazole metabolites were established and confirmed by comparison of HPLC retention times with the synthetic reference compounds and HPLC/mass spectrometry. Other metabolites were characterized by the masses of molecular ions. A significant fraction of the drug dose is biotransformed with the formation of hydroxylated benzimidazole moiety and oxidated morpholine.
Asunto(s)
Ansiolíticos/metabolismo , Bencimidazoles/metabolismo , Morfolinas/metabolismo , Animales , Ansiolíticos/sangre , Ansiolíticos/orina , Bencimidazoles/sangre , Bencimidazoles/orina , Biotransformación , Cromatografía Líquida de Alta Presión , Masculino , Espectrometría de Masas , Morfolinas/sangre , Morfolinas/orina , RatasRESUMEN
The pharmacokinetics of bemantan 2-(N-benzylamino)adamantane was studied in rat experiments by gas liquid chromatography after the drug was administered in a single dose per os or intraperitoneally. It has been shown that the drug per os is rapidly absorbed by the blood and enters the viscera, readily penetrates the blood-brain barrier. Intraperitoneal administration of the drug in the form of a starch suspension delays the attainment of the maximum drug blood level. With both routes of administration the drug rapidly disappears from the blood and organs. Small amounts of the unchanged drug are excreted in bound and free forms with urine. Rapid disappearance of the drug from the blood and organs is likely to be accounted for by its intensive metabolism, but the formation of conjugated metabolites and their binding to tissue structures.
