Isolation and structural characterization of the photolysis products of etoricoxib.
Etoricoxib is a potent and novel selective inhibitor of cyclooxygenase-2 (COX-2) which has been developed for the treatment of osteoarthritis, rheumatoid arthritis and several other inflammatory conditions. To support clinical pharmacokinetics studies, a method for the determination of etoricoxib in human plasma was developed. During the development of the method it was found that highly fluorescent products were formed when etoricoxib was exposed to UV light (254 nm). The formation of highly fluorescent products was the basis for the development of a highly sensitive HPLC/fluorescent assay for the indirect determination of etoricoxib in human plasma; the limit of quantification (LOQ) was 1 ng/mL. To unequivocally determine the chemical structures of the photolysis products of etoricoxib, a series of studies was conducted. When etoricoxib was irradiated online in a photochemical reactor, three products were detected in an HPLC-UV system. These products were characterized by HPLC-UV-fluorescence and HPLC-MS/MS. Possible structures of these products were proposed based on these data. The major photolysis products of etoricoxib were further isolated and their structures were elucidated using NMR and HPLC-NMR. The results of these experiments indicate that etoricoxib undergoes a photocyclization reaction when irradiated with UV light (254 nm), leading to the formation of two major isomeric photocyclization products.
Matthews
C Z
CZ
Department of Drug Metabolism, Merck Research Laboratories, West Point, PA, USA. catherine_matthews@merck.com
Subramanian
R
R
Woolf
E J
EJ
Foster
N
N
Matuszewski
B K
BK
D002851:Chromatography, High Pressure Liquid; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry*; D000077613:Etoricoxib; D007527:Isoenzymes / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009862:Online Systems; D010777:Photochemistry; D010782:Photolysis; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry*; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet; D013450:Sulfones / Q000737:chemistry*
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D011725:Pyridines; D013450:Sulfones; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000077613:Etoricoxib