Duloxetine is a potent and balanced dual inhibitor of serotonin and norepinephrine reuptake being investigated for the treatment of depression and urinary incontinence. The disposition of duloxetine was studied in four healthy human subjects after a single 20.2-mg (100.6 microCi) oral dose of [14C]duloxetine in an enteric-coated tablet. The mean total recovery of radioactivity (+/- S.E.M.) after 312 h was 90.5% (+/-0.4%) with 72.0% (+/-1.1%) excreted in the urine. Duloxetine was extensively metabolized to numerous metabolites primarily excreted into the urine in the conjugated form. The major biotransformation pathways for duloxetine involved oxidation of the naphthyl ring at either the 4-, 5-, or 6-positions followed by further oxidation, methylation, and/or conjugation. The major metabolites found in plasma were glucuronide conjugates of the following: 4-hydroxy duloxetine (M6), 6-hydroxy-5-methoxy duloxetine (M10), 4, 6-dihydroxy duloxetine (M9), and a sulfate conjugate of 5-hydroxy-6-methoxy duloxetine (M7). The major metabolites found in plasma were also found in the urine, but the urine contained many additional metabolites. In addition to duloxetine, 4-hydroxy duloxetine (M14) and an unidentified polar metabolite were observed in feces. Following [14C]duloxetine administration, Cmax was reached at a median of 6 h for both duloxetine and total radioactivity. Duloxetine accounted for less than 3% of the circulating radioactivity based on mean area under the curve values. The elimination half-life of total radioactivity (120 h) was substantially longer than that of duloxetine (10.3 h).