Metabolism And Excretion Of Imrecoxib In Rats

Imrecoxib, one of 3,4-diaryl-3-pyrrolin-2-ones, was synthesized by the Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, which is a specific inhibitor of cyclooxygenase-2 in developing. The metabolism and excretion of imrecoxib in rats are to be investigated in this paper and furthermore the cleavage pathways of imrecoxib and its main metabolites are to be deduced.1. Study on the metabolites of imrecoxib in ratsAfter oral administration of imrecoxib (30 mg ? kg ^-1), the urine and feces of four rats was collected. The samples were extracted by solid phase extraction column and were analyzed by gradient chromatography and liquid chromatography-multi-stage mass spectrometry. As a result, 14 metabolites were detected in all.In order to obtain reference substances of the metabolites, 13 L urine and 5 kg feces of 40 rats were collected and finally 5 phase I metabolites were separated from them. According to a new reaction we found, another metabolite (M5) was synthesized, whose amount is too little to separate from biosamples. Structures of all metabolites were confirmed by NMR and LC-MSⁿ data . In rats imrecoxib was mainly hydroxylated at C-5 (M5) or C-4'a (Ml) position or both C-5 and C-4'α position (M3). Ml and M3 can be further oxidized to M2 and M4. A metabolite that was reduced at C-3,4 position (M7) was also observed.Furthermore, one trace phase I metabolite (M6) and 8 phase II metabolites (M8～M15) were deduced according the cleavage pathways we summarized. Only glucuronide and glucoside conjugates were found and no sulfate conjugates were detected.2. Study on the ESI-MSⁿ of imrecoxib and its metabolitesTo investigate the characteristics of mass spectra of imrecoxib and its metabolites, their multi-stage MS were recorded on an electrospray ion trap mass spectrometer in the positive mode. All the 9 fragment pathways were deduced according their MSⁿ data or that of the isotope-labeled compound...