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

Combined liquid chromatography and electrospray mass spectrometry (LC/ ESI-MS) and tandem mass spectrometry (MS/MS) were used for the charact erization of the conjugated metabolites (glucuronides) of a new angiot ensin II receptor antagonist, candesartan cilexetil (TCV-116; (+/-)-1- (cyclohexyloxycarbonyloxy)ethyl henyl-4-yl]methyl}-1H-benzimidazole-7- carboxylate) in the plasma and bile of rats given the drug. The glucur onides of the active component, M-I (candesartan), in rat plasma and b ile were positional isomers with respect to the binding site of glucur onic acid The site of glucoronidation in M-I was not directly identifi ed by mass spectrometry. However, the structure of the isomers could b e elucidated by the MS/MS analysis of dimethylated glucuronides prepar ed by the reaction of glucuronide isomers with diazomethane: N-glucuro nide of M-I (M-I-NG) in the plasma and acyl glucuronide (M-I-AG) in th e 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.