Pharmacokinetics and Plasma Protein Binding of BRB-I-28, a Novel Antiarrhythmic Agent, in Dogs

Cardiovascular Drug Reviews

Sangiah

Berlin

et al. 1994

Self Cite

Key Words: 7-Benzyl-3-thia-7-azabicyclo[3.3. llnonane hydroperchlorate-class Ib antiarrhythmic agents.The Cardiac Arrhythmias Suppression Trial (CAST) was a recent placebo-controlled, randomized study designed to test the hypothesis that pharmacological suppression of asymptomatic or mildly symptomatic ectopic activity with class I agents would prevent lethal ventricular arrhythmias (18,42,43) during the first few months following myocardial infraction. The failure of class I antiarrhythmic drugs to reduce mortality (and the surprising finding of an increased incidence of sudden death for class Ic agents) caused the premature termination of CAST, thereby mandating a critical reexamination of the adequacy of existing pharmacological therapies for the suppression of ventricular arrhythmias. Presently, there are no antiarrhythmic agents possessing both a high efficacy for the suppression of potentially lethal ventricular arrhythmias and a low incidence of serious side effects (33,5334). Therefore, the development and therapeutic application of antiarrhythmic agents with specificity of action and tolerable systemic toxicity is a continuing challenge.In the last decade, 3,7-diheterabicyclo[3.3. llnonane (DHBCN) derivatives have been shown to possess potentially useful antiarrhythmic properties (26,28,55). Sparteine was the first compound of this family of heterocycles found to have class I antiarrhythmic activity (41). However, serious toxic effects such as nervousness, convulsions, and loss of muscular control limited its utility (34). Since that time, structure-activity relationships of a few bispidines [3,7-diazabicyclo[3.3. llnonane (28) which is a fragment from the inner ring system of the sparteine moiety] have been carefully examined (4,5,23,45,48, 5 1,56,57). Synthetic methodology to obtain a series DHBCN derivatives (4,5,23,56,57, Garrison GL, et al. Unpublished results) utilized a Mannich reaction. Selected derivatives ~~

Section: Effects On Mitochondria1 Respirationmentioning

confidence: 96%

“…HPLC analysis showed that the concentration range of BRB-1-28 was 0.24-4.3 mg/L in dogs following i.v. administration of 10 mg/kg (10,15). These data were best fitted to a two-compartment open model ( 15).…”

Section: Intravenous Kineticsmentioning

confidence: 99%

BRB‐I‐28: A Novel Class Ib Antiarrhythmic Agent

Cardiovascular Drug Reviews

Sangiah

Berlin

et al. 1994

Self Cite

“…Previous results have shown that BRB-I-28 has a bioavailability of only 44.5% in dogs, and may undergo extensive metabolism (14). To date, no studies have been reported on the metabolism of any member of the family of 3,7-diheterabicydo{3.3.1}-nonanes.…”

Section: Introductionmentioning

confidence: 95%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Eur. J. Drug Metab. Pharmacokinet.

Sangiah

Bourne

et al. 1995

Self Cite

The metabolism of BRB-I-28 (7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane), a novel class Ib antiarrhythmic agent, was characterized in vivo in dogs and rats and in vitro with rat liver microsomal preparations containing a NADPH-generating system. In dogs, rats and the in vitro hepatic microsomal oxidation system, BRB-I-28 was extensively metabolized to form 7-benzyl-3-thia-7-azabicyclo [3.3.1]nonane-3-oxide (I), a major metabolite. The metabolite I was produced via S-oxidation, presumably by the hepatic P-450 system. Formation of minor metabolite, 7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane (II) via the oxidation of the benzylic site was also identified in rats. Following intravenous and oral administration of BRB-I-28 to dogs, the plasma concentration of major metabolite I could be test described by a 1-compartmental model. The plasma AUC of metabolite I was 20% (i.v.) and 179.4% (oral) of that of the parent BRB-I-28, respectively, suggesting that BRB-I-28 was metabolized significantly by the first pass effect following oral administration. Extensive metabolism of BRB-I-28 to form metabolites I and II, which have demonstrated much lower antiarrhythmic activities, further supports previously observed pharmacodynamic and pharmacokinetic findings.

“…Additional characterization of electrophysiological effects of GLG-V-13 in normal and Chemical structure of GLG-V-13, 3-[4-(1H-imidazol-1-yl)benzoyl]-7-isopropyl-3,7-diazabicyclo[3.3.1] nonane dihydroperchlorate ischemically-injured myocardial cells is in progress (Patterson et al, unpublished data). The pharmacokinetic data demonstrated that GLG-V-13 has reasonably good oral bioavailability, wide distribution, and relatively slow elimination in dogs and rabbits [26]. In addition, this compound has a long duration of pharmacological effects, low proarrhythmic activity, and cardiodepressant actions.…”

Section: Introductionmentioning

confidence: 97%

Preliminary Acute and Subchronic Toxicity Studies of GLG-V-13, a Novel Class III Antiarrhythmic Agent, in Mice

Chandra

Kim

et al. 2011

Arzneimittelforschung

The acute and subchronic toxic effects of GLG-V-13 (3-[4-(1H-imidazol-1-yl)benzoyl]-7-isopropyl-3,7-diazabicyclo[3.3.1]nona ne dihydroperchlorate, CAS 155029-33-7), a novel class III with some class Ib antiarrhythmic activity, were investigated in mice. The estimated LD50 for GLG-V-13 given orally were 419 mg/kg for male mice and 383 mg/kg for female mice, respectively. The acute toxic signs appeared to be of the central nervous system in origin. Four groups of mice (15 per sex, group and dose) were fed daily with diets containing GLG-V-13 for 90 consecutive days. The equivalent daily doses were 0, 22, 50 and 121 mg/kg/day and 0, 27, 60 and 136 mg/kg/day for male and female mice, respectively. All of the mice survived. Food consumption was decreased. However, mean body weight and body weight gain were not significantly changed. Gross pathological changes, especially in the lungs and liver, were found in the middle and high dose groups. Consistent increased mean corpuscular hemoglobin concentration and decreased mean corpuscular hemoglobin were observed in all dose groups. Hepatocellular necrosis was found in both male and female mice treated with the drug and was dose-dependent. Marked vacuolation of the X zone in the adrenal gland with mild to moderate deposition of ceroid pigments (brown degeneration) was observed in female mice. Lesions in the kidneys and adrenal glands may be a possible reason for changes in serum sodium and potassium ions concentrations leading to an increase in water intake. A significant reduction in cholesterol in the high dose group may be a favorable pharmacological effect of GLG-V-13. The data from the 90-day subchronic toxicity studies indicate that GLG-V-13 appears to have limited systemic toxicity potential.