Characterization of Conjugated Metabolites of a New Angiotensin II Receptor Antagonist, Candesartan Cilexetil, in Rats by Liquid Chromatography/Electrospray Tandem Mass Spectrometry Following Chemical Derivatization

✍ Scribed by Kondo, Takahiro; Yoshida, Kiyoshi; Yoshimura, Yoshinobu; Motohashi, Michio; Tanayama, Shigeharu

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: English
• Weight: 500 KB
• Volume: 31
• Category: Article
• ISSN: 1076-5174
• DOI: 10.1002/(sici)1096-9888(199608)31:8<873::aid-jms368>3.0.co;2-j

✦ Synopsis

Combined liquid chromatography and electrospray mass spectrometry (LC/ESI-MS) and tandem mass spectrometry (MS/MS) were used for the characterization of the conjugated metabolites (glucuronides) of a new angiotensin I1 receptor antagonist, candesartan cilexetil (TCV-116; ( f )-l-(cyclohexyloxycarbony1oxy)ethyl 2-ethoxy-l-{ [ 2'-(1H-tetrazol-5-y1)biphenyl-4-yl1 methyl}-1 H-benzimidazole-7-carboxylate) in the plasma and bile of rats given the drug. The glucuronides of the active component, M-I (candesartan), in rat plasma and bile were positional isomers with respect to the binding site of glucuronic acid. The site of glucuronidation in M-I was not directly identified by mass spectrometry. However, the structure of the isomers could he elucidated by the MS/MS analysis of dimethylated glucuronides prepared by the reaction of glucuronide isomers with diazomethane: N-glucuronide of M-I (M-I-NG) in the plasma and acyl glucuronide (M-LAG) in the bile. The results obtained in this study indicated that LC/ESI-MS/MS analysis provides the detailed structure of conjugated metabolite by simple chemical derivatization.