Disposition of BRB-I-28 (7-benzyl-7-aza-3-thiabicyclo[3.3.1]nonane hydroperchlorate), a Novel Antiarrhythmic Agent

Abstract

SummaryThe aim of this study was to characterise the pharmacokinetic disposition and tissue distribution of BRB-I-28 (7-benzyl-7-aza-3-thiabicyclo[3.3.l)nonane hydroperchlorate) in rats. The pharmacokinetic disposition was studied by collecting blood samples before and at frequent intervals after intracardiac or oral administration of 14C-labelled BRB-I-28. Two-compartment and I-compartment pharmacokinetic models were used to describe blood concentration-time profiles after intracardiac and oral administration, respectively. After intracardiac administration, the half-life of elimination (t'l,~)from blood ranged from 4.66 to 9.91 hours and the apparent volume of distribution (V d(area» ranged from 3.131 to 6.239 L/kg. Oral dosing resulted in rapid and extensive absorption (bioavailability ± 80%). Distribution of radioactivity into heart, kidney, brain, liver, and perirenal fat was measured by sacrificing rats at various time intervals after oral administration of 14C-Iabelled BRB-I-28. Extensive distribution of radioactivity occurred in highly perfused organs, particularly liver, kidney and heart. However, levels of radioactivity in brain were low.BRB-I-28 (7-benzyl-7-aza-3-thiabicyclo[3.3.1] nonane hydroperchlorate) is a novel compound with antiarrhythmic properties. Preliminary studies in dogs show that it is more effective than lidocaine (lignocaine) in inhibiting the induction of sustained ventricular tachycardia (Bailey et aL 1974;Scherlag et aL 1988). Furthermore, it suppresses ventricular arrhythmias caused by reentry, an electrophysiological aberration that is associated closely with sudden death in patients suffering from coronary heart disease. In contrast to lidocaine and most other antiarrhythmic agents that depress haemodynamics, BRB-I-28 causes a moderate increase in blood pressure. The therapeutic potential of any pharmacological agent can be assessed in terms of its therapeutic index. The margin of safety depends on the inherent toxicity of the agent and dispositional factors that determine drug concentrations in tissues of toxicological or therapeutic significance. The goals of this study were to determine pharmacokinetic values for BRB-I-28 after oral and intracardiac administration and to study the time-related distribution of the drug into brain, heart, kidney, liver and perirenal fat. ORIGINAL RESEARCH ARTICLE

Synthesis and structure of 7-alkoxyalkyl-3-thia-7-zabicyclo[3.3.1]nonan-9-ones and several of their derivatives

“…In a study of the properties of these compounds as local anesthetics, we found that 7-(3-butoxypropyl)-3thia-7-azabicyclo[3.3.1]nonane hydrochloride (10) [11] is superior to the lidocaine standard in duration of anesthesia. As expected [12,13], the 7-alkoxyalkyl-3-thia-7-azabicyclo[3.3.1]nonane products have antiarrhythmic activity. Of all the compounds compared, the most active compound preventing calcium chlorideinduced cardiac arrhythmia and on a model of fatty occlusion of the coronary artery is 7-(2-ethoxyethyl)-3-thia-7-azabicyclo[3.3.1]nonane (8) [9].…”

“…C (11) C (12) C (13) The 13 C NMR spectra of the pure isomers given in Table 2 lack a singlet for the carbonyl carbon atom but show a doublet for C (9) at 68.2-72.3 ppm. The 13 C NMR spectra of 14 and 15, which are unresolved isomer mixtures, show doubling of the carbon atom signals for the ring and substituent.…”

Metabolism and metabolite pharmacokinetics of BRB-I-28, a class Ib antiarrhythmic agent

“…Pharmacokinetic and tissue distribution profiles of BRB-I-28 in rats (13) and in dogs (14) have been examined. Previous results have shown that BRB-I-28 has a bioavailability of only 44.5% in dogs, and may undergo extensive metabolism (14).…”