title: Metabolism and metabolite pharmacokinetics of BRB-I-28, a class Ib antiarrhythmic agent.
abstract: 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.
authors.affiliation: Department of Physiological Science, Oklahoma State University, Stillwater 74078, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Chen
authors.forename: S
authors.initials: S
authors.lastname: Sangiah
authors.forename: D W
authors.initials: DW
authors.lastname: Bourne
authors.forename: J D
authors.initials: JD
authors.lastname: Roder
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.forename: F K
authors.initials: FK
authors.lastname: Alavi
authors.forename: C R
authors.initials: CR
authors.lastname: Clarke
authors.forename: G L
authors.initials: GL
authors.lastname: Garrison
authors.forename: K D
authors.initials: KD
authors.lastname: Berlin
authors.forename: K M
authors.initials: KM
authors.lastname: Couch
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism* / Q000493:pharmacokinetics*; D001711:Biotransformation; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism* / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000889:Anti-Arrhythmia Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C041492:7-benzyl 3-thia-7-azabicyclo(3.3.1)nonane