METABOLISM AND METABOLITE PHARMACOKINETICS OF BRB-I-28, A CLASS IB ANTIARRHYTHMIC AGENT

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 cont aining a NADPH-generating system. In dogs, rats and the in vitro hepat ic microsomal oxidation system, BRB-I-28 was extensively metabolized t o 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 a minor metabolite, 7-benzoy l-3-thia-7-azabicyclo[3.3.1]nonane (II) via the oxidation of the benzy lic site was also identified in rats. Following intravenous and oral a dministration of BRB-I-28 to dogs, the plasma concentration of major m etabolite I could be best described by a I-compartmental model. The pl asma AUC of metabolite I was 20% (i.v.) and 179.4% (oral) of that of t he parent BRB-I-28, respectively, suggesting that BRB-I-28 was metabol ized significantly by the first pass effect following oral administrat ion. Extensive metabolism of BRB-I-28 to form metabolites I and II, wh ich have demonstrated much lower antiarrhythmic activities, further su pports previously observed pharmacodynamic and pharmacokinetic finding s.