SummaryThe pharmacokinetics and plasma protein binding of BRB-I-28, a novel antiarrhythmic agent, were investigated in dogs. The plasma concentration-time profile of BRB-I-28, following an intravenous bolus dose of 10 mgJkg, can be adequately described by a 2-compartment open model. The mean volume of distribution at steady-state (Vdss) was 8.759 L/kg, the mean total systemic clearance (CL) was 1.289 ml/h/kg, and the mean elimination half-life (t' 12/1) was 4.645 hours. Following intravenous administration, approximately 1.85% of the dose was excreted in the urine (0 to 48 hours) as parent drug. Changes in plasma concentrations, after oral administration of BRB-I-28 20 mgJkg, were best described by a l-compartment open model. BRB-I-28 was rapidly absorbed (tmax = 1.22 hours and Cmax = 1.59 mgJL) with a rapid elimination rate (t'12kel = 1.583

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