Pharmacokinetics and plasma protein binding of the new potent class III antiarrhythmic agent 3-[4-(1H-imidazol-1-yl)benzoyl]-7-isopropyl-3, 7-diazabicyclo[3.3.1]nonane dihydroperchlorate.

GLG- V-13 (3-[4- (1H-imidazol-1-yl) benzoyl]-7-isopropyl- 3, 7- diazabicyclo [3.3.1] nonane dihydroperchlorate, CAS 155029-33-7) has been shown to be a potent class III antiarrhythmic agent. The oral and intravenous pharmacokinetics and plasma protein binding of GLG-V-13 in dogs and in rabbits have now been investigated. Plasma GLG-V-13 concentration-time profiles, following an i.v. bolus dose of 6 mglkg, were fitted to a 2-compartment model. The volume of distribution at steady state (V d(ss) , the total systemic (Cl B ), and the elimination half-life (t 1/2β ) were 4.441 l/kg, 1.113 l/h/kg, and 2.485 h in dogs and 3.723 llkg, 1.548 l/h/kg, and 1.401 h in rabbits. Following i.v. dosing, approximately 9.38 % of the parent compound was excreted in dogs urine (0-72 h). Changes in plasma GLG-V-13 concentrations, after oral administration of GLG-V-13 (6 mg/kg ), were best described by the l-compartment pharmacokinetic model. The t max and C max were 1.69 h, 0.54 mgll in dogs and 1.44 h, 0.35 mgll in rabbits. On oral administration, GLG- V-13 was moderately eliminated (t 1/2kel' p.867 h -1 in dogs and 3.961 h -1 in rabbits, respectively). Oral bioavailability was estimated to be 53.2 % ± 11.3 % in dogs and 66.7% ± 7.7% in rabbits. About 8.74 % of the oral dose (6 mg/kg ) was excreted via the dog urine (0-72 h). In vitro binding of GLG-V-13 to dog plasma protein was 29.4 4 ± 9.90% (from 0.5 to 4 mgll). Ex vivo binding of GLG-V-13 to dog plasma protein was 10.4 ± 7.20%. Reasonably good oral bioavailability, prolonged antiarrhythmic properties, and the lack of proarrhythmic effects make this agent worthy of further study