RT Journal Article
SR Electronic
T1 METABOLISM, EXCRETION, AND PHARMACOKINETICS OF DULOXETINE IN HEALTHY HUMAN SUBJECTS
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1142
OP 1150
DO 10.1124/dmd.31.9.1142
VO 31
IS 9
A1 R. J. Lantz
A1 T. A. Gillespie
A1 T. J. Rash
A1 F. Kuo
A1 M. Skinner
A1 H-Y. Kuan
A1 M. P. Knadler
YR 2003
UL http://dmd.aspetjournals.org/content/31/9/1142.abstract
AB 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 μCi) 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). The American Society for Pharmacology and Experimental Therapeutics