The metabolism of fluvoxamine to fluvoxamino acid is known to involve a two-step oxidation process via an alcohol intermediate, fluvoxamino alcohol. The present study was carried out to identify the cytochrome P450 (CYP) enzyme(s) involved in the metabolism offluvoxamine to fluvoxamino alcohol using human liver microsomes and cDNA-expressed human CYP enzymes. The mean Km and Vmax values for the formation of fluvoxamino alcohol from fluvoxamine in human liver microsomes were 76.3 microM and 37.5 pmol min(-1) mg(-1) protein, respectively. The formation of fluvoxamino alcohol from fluvoxamine in pooled human liver microsomes was significantly inhibited by quinidine, a relatively specific CYP2D6 inhibitor, with a Ki value of 2.2 microM, whereas other several relatively specific CYP inhibitors did not inhibit the formation of fluvoxamino alcohol. In addition, only CYP2D6 of several cDNA-expressed human CYP enzymes examined showed substantial activity for the formation of fluvoxamino alcohol. Furthermore, the formation of fluvoxamino acid from fluvoxamino alcohol is potently inhibited by 4-methylpyrazole in human liver cytosol. These data suggest that CYP2D6 is the only enzyme predominantly responsible for the first-step oxidation of fluvoxamine to fluvoxamino alcohol, and alcohol dehydrogenase is involved in the second-step oxidation of fluvoxamino alcohol to the corresponding carbolic acid.