PHARMACOKINETICS AND PLASMA-PROTEIN BINDING OF THE NEW POTENT CLASS-III ANTIARRHYTHMIC AGENT BENZOYL]-7-ISOPROPYL-3,7-DIAZABICYCLO[3.3.1]NONANE DIHYDROPERCHLORATE

GLG-V-13 midazol-1-yl)benzoyl]-7-isopropyl-3,7-diazabicyclo [3.3.1] no nane dihydroperchlorate, CAS 155029-33-7) has been shown to be a poten t class III antiarrhythmic agent. The oral and intravenous pharmacokin etics and plasma protein binding of GLG-V-13 in clogs and in rabbits h ave now been investigated. Plasma GLG-V-13 concentration-time profiles , following an iv bolus dose of 6 mg/kg, were fitted to a 2-compartmen t model. The volume of distribution at steady state (V-d(SS)), the tot al systemic (Cl-B), and the elimination half-life (t(1/2 beta)), were 4.441 l/kg, 1.113 l/h/kg, and 2.485 h in dogs and 3.723 l/kg, 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 1-compartment pharmacokinetic model The t(max) and C-max were 1.69 h, 0.54 mg/l in dogs and 1.44 h, 0.35 mg/l in rabbits. On oral administration, GLG-V-13 was moderately eliminated (t(1/2kel), 1.867 h(-1) in clogs and 3.961 h(-1) in rabbit s respectively). Oral bioavailability was estimated to be 53.2% +/- 11 .3% in dogs and 66.7% +/- 77% in rabbits. About 8.74% of the oval dose (6 mg/kg) was excreted via the dog urine (0-72 h). In vitro binding o f GLG-V-13 to dog plasma protein was 29.4 +/- 9.90% (from 0.5 to 4 mg/ l). Ex vivo binding of GLG-V-13 to dog plasma protein was 10.4 +/- 7.2 0%. Reasonably good oral bioavailability, prolonged antiarrhythmic pro perties, and the lack of proarrhythmic effects make this agent worthy of further study.