High-performance liquid chromatographic determination of BRB-I-28, a novel antiarrhythmic agent, in dog plasma and urine

Chen, C. L.; Lesseley, B. A.; Clarke, Cyril R.; Roder, Joseph D.; Sangiah, S.; Berlin, K. Darrell; Garrison, G. L.; Scherlag, Benjamin J.; Lazzara, Ralph; Patterson, Eugene

doi:10.1016/0378-4347(92)80565-8

Cited by 9 publications

(2 citation statements)

References 2 publications

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“…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

Chen

Sangiah

Berlin

et al. 1994

Cardiovascular Drug Reviews

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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 ~~

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Section: Intravenous Kineticsmentioning

confidence: 99%

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

Chen

Sangiah

Berlin

et al. 1994

Cardiovascular Drug Reviews

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“…The parent BRB-I-28 and its metabolite(s) were separated and quantitated with previously reported conditions (20,21). Possible metabolite peaks were collected from HPLC analysis and extracted with chlorofonn.…”

Section: Hplc Separation and Analysismentioning

confidence: 99%

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

Chen

Sangiah

Bourne

et al. 1995

Eur. J. Drug Metab. Pharmacokinet.

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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.

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

et al. 1993

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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

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High-performance liquid chromatographic determination of BRB-I-28, a novel antiarrhythmic agent, in dog plasma and urine

Cited by 9 publications

References 2 publications

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

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

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

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

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