title: Quantitative determination of diol metabolites of CS-670, a new antiinflammatory agent, by capillary column gas chromatography-mass spectrometry.
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.
authors.affiliation: Analytical and Metabolic Research Laboratories, Sankyo Co., Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Asami
authors.forename: M
authors.initials: M
authors.lastname: Yamamura
authors.forename: W
authors.initials: W
authors.lastname: Takasaki
authors.forename: Y
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000652:urine*; D002138:Calibration; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods*; D008297:Male; D051379:Mice; D010666:Phenylpropionates / Q000737:chemistry / Q000652:urine*; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013237:Stereoisomerism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D010666:Phenylpropionates; C040375:pelubiprofen