Metabolism of the alpha-1A-adrenergic receptor antagonist, pyridine-phenylpiperazine analog (RWJ-69597), in rat, dog and human hepatic S9 fractions -API-MS/MS identification of metabolites.

ABSTRACT

The In vitro metabolism of the alpha-1A-adrenergic antagonist, RWJ-69597, an analog of pyridine-phenylpiperazines, was conducted after incubation with rat, dog and human hepatic S9 fractions in the presence of an NADPH-generating system. Unchanged RWJ-69597 (> or =43% of the sample in all species) plus 9 metabolites were profiled, quantified, and tentatively identified on the basis of API-MS and MS/MS data. The four metabolic pathways for the formation of RWJ-69597 metabolites are 1. methyl/phenyl/piperazinylhydroxylation, 2. N/Odealkylation, 3. N-dephenylation, and 4. dehydration. Pathway 1 formed 1 major (8-36%) and 3 minor (<1-3%) hydroxylated metabolites. Pathway 2 produced 2 moderate/minor N/O-dealkylated metabolites (<1- < or =11%), and in conjunction with pathway 1, formed 1 minor diol metabolites (< or =2%). Pathways 3 and 4 generated 2 minor metabolites, N-desphenyl RWJ-69597 (< or =4%) and dehydrated RWJ-69597 (< or =2%), respectively. RWJ-69597 is more extensively metabolized in the rat than the dog or the human in this hepatic system.