Identification of major metabolites of the catechol-O-methyltransferase-inhibitor nitecapone in human urine.
Metabolites of nitecapone [3-(3,4-dihydroxy-5-nitrobenzylidene)-2,4-pentanedione], a potent new catechol-O-methytransferase-inhibitor, were isolated from human urine both after hydrolysis with beta-glucuronidase and as intact conjugates. Seven phase-I metabolites and corresponding glucuronides were identified using electron ionization and fast atom bombardment mass spectrometry, IR spectroscopy, and proton NMR spectrometry. The most abundant metabolite in urine was the glucuronide of unchanged nitecapone, representing 60-65% of the metabolites found. The main phase-I metabolic reaction was reduction of the side chain double bond and carbonyl groups. One of the major metabolites was formed by cleavage of the side chain by retro aldol condensation. All phase-I metabolites were present mainly as their glucuronic acid conjugates. The 3-nitrocatechol-structure of nitecapone seems to hinder nitro-reduction, catechol-O-methylation, and sulfation reactions.
Taskinen
J
J
Orion Pharmaceutica, Research Center, Espoo, Finland.
Wikberg
T
T
Ottoila
P
P
Kanner
L
L
Lotta
T
T
Pippuri
A
A
Bäckström
R
R
D000284:Administration, Oral; D000328:Adult; D001711:Biotransformation; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000378:metabolism* / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010422:Pentanones / Q000378:metabolism* / Q000652:urine; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet
D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D010422:Pentanones; C057364:nitecapone