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

European Journal of Drug Metabolism and Pharmacokinetics
C L ChenK M Couch

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 pharmacokine...Continue Reading

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Citations

Aug 10, 2000·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·C L ChenR Lazzara
Mar 7, 2009·Regulatory Toxicology and Pharmacology : RTP·Huiqing HuYanfang Xu
May 21, 2015·European Journal of Drug Metabolism and Pharmacokinetics·Yan ZhaoShijie Wang
Feb 14, 2007·Journal of Abnormal Child Psychology·Karen AppleyardL Alan Sroufe
Jan 20, 2005·American Journal of Physiology. Endocrinology and Metabolism·Anne Lene Dalkjaer RiisNiels Møller

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