ABSTRACT
Plasma concentrations of BMS-184111, an anxiolytic, were determined as a function of time following single intravenous, intraperitoneal and oral administrations. In order to assess the brain penetration of this compound, concentrations in whole brain samples were also determined in the intravenous leg of the study. Concentrations of BMS-184111 in plasma and brain homogenate samples were determined using an HPLC assay following liquid/liquid extraction. After intravenous administration, BMS-184111 was eliminated from plasma with a half-life of about 3.6 hours. The brain/plasma AUC ratio for BMS-184111 concentration was 5.5, indicating effective penetration of the compound into the brain. Comparison of the plasma AUC values obtained following intravenous and intraperitoneal doses indicated that BMS-184111 was only 33% bioavailable after intraperitoneal administration, suggesting that the compound undergoes significant first-pass hepatic extraction. The oral bioavailability of BMS-184111 was found to be 10% after administration of the free base and 23% after administration of the hydrochloride salt. These results suggest that BMS-184111 undergoes incomplete GI absorption and/or intestinal metabolism in addition to first-pass hepatic extraction. The in vitro metabolism of BMS-184111 was studied using rat liver homogenate preparation (the 9000 g supernatant; S-9). Several of the metabolites thus generated were profiled using LC/MS and LC/MS/MS. Metabolism of BMS-184111 in rat liver S-9 occurs through hydroxylation, O-demethylation, and demethylenation.
Subject(s)
Anti-Anxiety Agents/pharmacokinetics , Dioxoles/pharmacokinetics , Piperidines/pharmacokinetics , Animals , Anti-Anxiety Agents/analysis , Chromatography, High Pressure Liquid , Dioxoles/analysis , Male , Mass Spectrometry , Piperidines/analysis , Rats , Rats, Sprague-DawleySubject(s)
Brain/ultrastructure , Receptors, Serotonin/metabolism , Serotonin/analogs & derivatives , Animals , Binding Sites , Binding, Competitive , Brain/metabolism , Cerebral Cortex/metabolism , Cerebral Cortex/ultrastructure , Corpus Striatum/metabolism , Corpus Striatum/ultrastructure , Guinea Pigs , In Vitro Techniques , Radioligand Assay , Serotonin/metabolism , TritiumABSTRACT
The synthesis and biodistribution properties of 99mTc-labeled 5-substituted N-(3-cyano-4-methyl-2-pyrrylcarbamoylmethyl)iminodiacetic acids and a similar series of N1-methyl analogs are described. These compounds were compared with 99mTc-labeled N-(2,6-dimethylphenylcarbamoylmethyl)iminodiacetic acid for hepatobiliary activity in the rat. The effects of structural modifications on biological activity are also reported.
Subject(s)
Biliary Tract/diagnostic imaging , Imino Acids , Liver/diagnostic imaging , Technetium , Animals , Chemical Phenomena , Chemistry , Imino Acids/chemical synthesis , Isotope Labeling , Male , Radionuclide Imaging , Rats , Rats, Inbred Strains , Tissue DistributionABSTRACT
The synthesis, local anesthetic and antiarrhythmic properties, and CNS toxicity of 19 2-(2-alkylaminoalkylamido)pyrroles are described. Most of the compounds exhibited local anesthetic activity by the guinea pig wheal test, and four showed activity comparable to or greater than that of lidocaine. Most compounds also exhibited antiarrhythmic activity; five compounds had activity comparable to that of lidocaine, and one was more potent. All compounds exhibiting antiarrhythmic activity also were toxic to the central nervous system.
Subject(s)
Anesthetics, Local/chemical synthesis , Anti-Arrhythmia Agents/chemical synthesis , Pyrroles/chemical synthesis , Amides/chemical synthesis , Amides/pharmacology , Animals , Chemical Phenomena , Chemistry , Guinea Pigs , Heart Rate/drug effects , Pyrroles/pharmacology , Skin TestsABSTRACT
N-(3-Cyano-4,5-dimethyl-2-pyrrylcarbamoylmethyl)iminodiacetic acid (IIa) and N-(3-cyano-4-methyl-5-benzyl-2-pyrrylcarbamoylmethyl)iminodiacetic acid (IIb) were synthesized, labeled with technetium 99m, and compared with 99mTc-labeled p-isopropylacetanilidoiminodiacetic acid (I) for hepatobiliary activity in rats. All three compounds showed similar clearance of radioactivity from the blood. Comparison of the amount of radioactivity in various organs 1 hr after injection showed no significant difference between I and IIb. Compound IIa showed significantly less radioactivity in the GI tract and a higher amount in the kidneys and bladder.