Identification of metabolite profiles of the catechol-O-methyl transferase inhibitor tolcapone in rat urine using LC/MS-based metabonomics analysis.
The process of drug metabolite identification is extremely important for drug efficacy, safety and pharmacokinetics. The traditional method usually involves using a drug with a radioactive labeled nuclei and/or isolating major drug metabolites by HPLC before applying MS and NMR analyses, which requires trained specialists to handle the radioactive compounds and is time consuming for offline-HPLC separation. A method using mass spectrometry-based metabonomics combined with multivariate statistical analysis was applied to rapidly identify metabolite profiles of tolcapone, a catechol-O-methyl transferase inhibitor for Parkinson's disease treatment. The tolcapone metabolites were identified based on the accurate mass measurement (<3 ppm) and MS(2) mass spectrum. In total, 16 tolcapone metabolites were detected and identified, 6 of which have not been reported previously. Our results indicate that the method has the capability to accelerate the process of identifying drug metabolites, ultimately reduce drug development costs, and make the process safer without requiring a drug with radioactive nuclei. Most importantly, the assay can detect the major and minor drug metabolites in a global view. Furthermore, since tolcapone has been associated with idiosyncratic drug induced liver toxicity the rapid detection of tolcapone-related metabolites can provide mechanistic toxicity information related to drug metabolism and the formation of reactive drug metabolites.
Sun
Jinchun
J
Division of Systems Toxicology, National Center for Toxicological Research, FDA, Jefferson, AR 72079, USA.
Von Tungeln
Linda S
LS
Hines
Wade
W
Beger
Richard D
RD
D000818:Animals; D001577:Benzophenones / Q000652:urine*; D065098:Catechol O-Methyltransferase Inhibitors; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004791:Enzyme Inhibitors / Q000652:urine*; D005260:Female; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*; D055432:Metabolomics; D009596:Nitrophenols / Q000652:urine*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077867:Tolcapone
D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D004791:Enzyme Inhibitors; D009596:Nitrophenols; D000077867:Tolcapone