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Metabolites of entacapone [(E)-2-cyano-N,N-diethyl-3-(3,4-dihydroxy-5-nitrophenyl)propenamide++ +], a potent inhibitor of catechol-O-methyltransferase, were isolated from human and rat urine. After hydrolysis of glycosides and sulfates, four human and eight rat metabolites were identified, in addition to unchanged entacapone by HPLC with diode-array UV detection, electron ionization mass spectrometry, and IR spectroscopy. In man 10% of an oral dose was excreted in urine during 8 hr. The glucuronides of entacapone and its (Z)-isomer represented about 70 and 25% of the urinary metabolites, respectively. The (Z)-isomer of entacapone and two less abundant urinary metabolites, formed through cleavage or reduction of the side chain carbon-carbon double bond, were also formed in an erythrocyte incubation. The (Z)-isomer was the only phase I metabolite found in addition to entacapone in human plasma. The nitro group of entacapone seems to hinder methylation of the catechol hydroxyls in man, because no methylation products were detected. Twenty-four hr after iv administration of 14C-labeled entacapone to rats, over 50% was excreted in the feces and approximately 35% extensively metabolized in the urine. Entacapone and its phase I metabolites were excreted mainly as glucuronides and sulfates in rat urine. The most abundant urinary metabolite was the glucuronide of entacapone. Unchanged, N-dealkylated, and O-methylated entacapone, the (Z)-isomer of entacapone, and 3,4-dihydroxy-5-nitrobenzaldehyde were found in both plasma and urine from rats. Two minor urinary metabolites were formed through reduction of the side chain carbon-carbon double bond and through acetylation of the amino group resulting from nitro reduction.