Pharmacokinetic, pharmacodynamic, and toxicological studies on new antiarrhythmic agents from selected 3,7-diheterabicyclo(3.3.1)nonane derivatives

Scope of study. The objectives of this study were (1) to develop high-performance liquid chromatographic (HPLC) methods for the determination of selected 3,7-diheterabicyclo (3.3.1) nonane derivatives, BRB-I-28 (I), a soluble form of BRB-I-28 (II), and GLG-V-13 (III) in biological fluids; (2) to characterize absorption, distribution, metabolism, and elimination (pharmacokinetic) profiles of these novel antiarrhythmic agents in animals and to identify major metabolites in biological fluids; (3) to determine the effects of these agents on myocardial microsomal Na;Findings and conclusions. Several HPLC techniques with UV detection have been developed to determine concentrations of I-III and their metabolite(s) in biological fluids. All of these methods have been successfully applied to pharmacokinetic studies in dogs and rabbits. Compounds I-III exhibit pharmacokinetic profiles characteristic of one-compartment and two-compartment open models after oral and intravenous administration, respectively. These new antiarrhythmic agents have fairly good absorption, wide distribution, relatively low protein binding, extensive metabolism, and intermediate rates of elimination. Two metabolites of I/II have been identified in vivo in animals and in vitro hepatic microsomal system. These antiarrhythmic agents have dose-dependent inhibitory effects on Na...