Characterization of metabolites of Celecoxib in rabbits by liquid chromatography/tandem mass spectrometry.
The metabolism of the anti-inflammatory drug Celecoxib in rabbits was characterized using liquid chromatography (LC)/tandem mass spectrometry (MS/MS) with precursor ion and constant neutral loss scans followed by product ion scans. After separation by on-line liquid chromatography, the crude urine samples and plasma and fecal extracts were analyzed with turbo-ionspray ionization in negative ion mode using a precursor ion scan of m/z 69 (CF(3)) and a neutral loss scan of 176 (dehydroglucuronic acid). The subsequent product ion scans of the [M - H] ions of these metabolites yielded the identification of three phase I and four phase II metabolites. The phase I metabolites had hydroxylations at the methyl group or on the phenyl ring of Celecoxib, and the subsequent oxidation product of the hydroxymethyl metabolite formed the carboxylic acid metabolite. The phase II metabolites included four positional isomers of acyl glucuronide conjugates of the carboxylic acid metabolite. These positional isomers were caused by the alkaline pH of the rabbit urine and were not found in rabbit plasma. The chemical structures of the metabolites were characterized by interpretation of their product ion spectra and comparison of their LC retention times and the product ion spectra with those of the authentic synthesized standards.
Zhang
J Y
JY
Metabolism and Safety Evaluation (MSE), Pharmacia, Skokie, IL 60077, USA. ji.y.zhang@monsanto.com
Wang
Y
Y
Dudkowski
C
C
Yang
D c
Dc
Chang
M
M
Yuan
J
J
Paulson
S K
SK
Breau
A P
AP
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D000068579:Celecoxib; D002853:Chromatography, Liquid / Q000379:methods*; D005243:Feces / Q000737:chemistry; D005260:Female; D020719:Glucuronides / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000652:urine; D006863:Hydrogen-Ion Concentration; D013058:Mass Spectrometry / Q000379:methods*; D015394:Molecular Structure; D011720:Pyrazoles; D011817:Rabbits; D012015:Reference Standards; D013237:Stereoisomerism; D013449:Sulfonamides / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine
D000894:Anti-Inflammatory Agents, Non-Steroidal; D020719:Glucuronides; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib