title: Biopharmaceutical characterization of 450191-S, a ring-opened derivative of 1,4-benzodiazepine. II. Evidence for reduced first-pass extraction by rat liver.
abstract: The new hypnotic, 5-[(2-aminoacetamido)methyl]-1-[p-chloro-2-(o- chlorobenzoyl)phenyl]-N,N-dimethyl-1H-1,2,4-triazole-3-carboxamide hydrochloride dihydrate (450191-S), is a ring-opened derivative of 1,4-benzodiazepine that is activated by spontaneous cyclization via a labile desglycylated metabolite (191DG). Pharmacokinetic comparison between 450191-S and its primary active metabolite, 8-chloro-6-(2-chlorophenyl)-N,N-dimethyl-4H-1,2,4-triazole[1,5-a][1,4] benzodiazepine-2-carboxamide (M-1), in rats revealed that higher levels of active metabolites were produced after 450191-S administration. To find the causes for this, in vivo and in vitro experiments were performed with the focus on hepatic uptake. Study of the absorption and distribution of radioactivity after intraduodenal administration of [14C]450191-S and [14C]M-1 revealed that most of the radioactivity was in the liver, with absorption of M-1 being rapid regardless of the dose and the absorption of 450191-S being slower at higher doses. Comparison of the portal and systemic metabolite levels showed the hepatic first-pass extraction after M-1 administration to be more effective than that after 450191-S administration. This was attributed to the labile intermediate, 191DG, which reduced the first-pass extraction in the liver. This reduction was confirmed by pharmacokinetic analysis after portal injection of 191DG in vivo and by incubation with liver slices in vitro. Thus, the presence of 191DG improved the bioavailability of active metabolites after 450191-S administration.
mesh_terms: D000818:Animals; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D014018:Tissue Distribution; D014230:Triazoles / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D014230:Triazoles; C049547:8-chloro-6-(2-chlorophenyl)-N,N-dimethyl-4H-1,2,4-triazolo(1,5-a)(1,4)benzodiazepine-2-carboxamide; C041075:rilmazafone