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 characterization of the conjugated metabolites (glucuronides) of a new angiotensin II receptor antagonist, candesartan cilexetil (TCV-116; (+/-)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-¿[2'-(1H-tetrazol-5-yl)biphenyl- 4-yl]methyl¿-1H-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 be 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-I-AG) 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.
Kondo
T
T
Pharmaceutical Development Division, Takeda Chemical Industries Ltd., Osaka, Japan.
Yoshida
K
K
Yoshimura
Y
Y
Motohashi
M
M
Tanayama
S
S
D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000032:analysis* / Q000737:chemistry / Q000493:pharmacokinetics; D001646:Bile / Q000737:chemistry; D001711:Biotransformation; D001713:Biphenyl Compounds / Q000032:analysis* / Q000737:chemistry / Q000493:pharmacokinetics; D002853:Chromatography, Liquid; D005965:Glucuronates / Q000032:analysis; D008297:Male; D013058:Mass Spectrometry; D008745:Methylation; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D005965:Glucuronates; D013777:Tetrazoles; D000804:Angiotensin II; C077793:candesartan cilexetil