Metabolic fate of the novel antihypertensive drug naftopidil.

The metabolism of 14C-naftopidil ((R,S)-1-(2-methoxyphenyl)-1-piperazinyl-3- (1-naphthyl-oxy-2-propanol, CAS 57149-07-2) and the pharmacodynamic action of the metabolites was investigated. The metabolic pathway in rat, dog, mouse and man was qualitatively similar, with preference for the hydroxylation of the phenyl or naphthyl moiety of naftopidil [phenyl)hydroxy-metabolite, (naphthyl)hydroxy-metabolite). Cleavage of the parent compound and production of the propylene glycol metabolite was a further important reaction especially for rat and man. In all species investigated, demethylation of naftopidil occurs to a minor extent. O-desmethyl-naftopidil, (phenyl)hydroxy-naftopidil and (naphthyl)hydroxy-naftopidil were found to have similar affinities for the alpha 1-adrenoceptors as the parent compound (IC50)nmol/l): 433.0; 585.0; 52.7; respectively; naftopidil: 235.0). The naftopidil metabolites, like the parent compound showed no alpha 2- or beta-adrenoceptor affinity.