Quantitative determination of diol metabolites of CS-670, a new antiinflammatory agent,by capillary column gas chromatography-mass spectrometry |
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| Affiliation: | 1. Department of Sanitary Technology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, PR China;2. Chengdu Center for Disease Control and Prevention, Chengdu 610047, PR China;3. Sichuan Center for Disease Control and Prevention, Chengdu 610044, PR China;1. Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, PR China;2. Municipal Key Laboratory of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, PR China;1. Guangdong Provincial Key Laboratory of Petrochemical Pollution Processes and Control, School of Environmental Science and Engineering, Guangdong University of Petrochemical Technology, Maoming 525000, Guangdong, China;2. School of Environment and Energy, South China University of Technology, Guangzhou 510006, Guangdong, China;3. Department of Environmental Science, Zhejiang University, Hangzhou, Zhejiang 310058, China;1. Department of Environmental Science, Zhejiang University, Hangzhou, 310058, China;2. Zhejiang Provincial Key Laboratory of Organic Pollution Process and Control, Hangzhou, 310058, China |
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| Abstract: | CS-670(I), being developed as a non-steroidal anti-inflammatory agent, is a racemic prodrug. It has been found to be readily metabolized to active metabolites: trans and unsaturated mono-ols (trans-OH, unsaturated-OH). We report here a method for the quantitative determination of the eight diol stereoisomers excreted in urine after administration I. The diols were well separated and quantitated using capillary column GC-MS after a rather simple derivatization with diazomethane-trifluoroacetic anhydride. Sex differences in rats and species differences between rats and mice were observed in the metabolism of I: the trans-diols originating from trans-OH were predominantly excreted in male and female rat urine but the excretion rate was greater in the male rats; the cis-diols originating from cis mono-ol (cis-OH) were the major urinary metabolites in mice. The hydroxy groups were mainly introduced at the respective equatorial hydrogen atoms at the 4′-carbon of trans-OH and the 5′-carbon of cis-OH. The 4′- and 5′-hydroxy groups in the diols were in the cis conformation with respect to the original 2′-hydroxy group. As approximately 9% of the trans-diols were excreted in urine after administration of cis-OH to rats, the chiral inversion from cis-OH to trans-OH was suggested to occur through the saturated ketone intermediate. |
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