title: Stereoselectivity of the phase-II-metabolism of the H1 antihistaminic drug dimethindene investigated by capillary electrophoresis.
abstract: Two capillary electrophoretic (CE) methods for the determination of conjugated metabolites of the antihistaminic drug dimethindene were developed. These methods allow the determination of the diastereomeric ratios of both Phase II glucuronides, 6-hydroxy dimethindene glucuronide (5) and 6-hydroxy-N-demethyl dimethindene glucuronide (6). Furthermore, after enzymatic deconjugation of both glucuronides, enantiomeric ratios of the hydroxylated Phase I metabolites 3 and 4 were determined. For comparison, glucuronides 5 and 6 were prepared by enzymatic synthesis and identified by MALDI-TOF mass spectrometry and deconjugation with beta-glucuronidase to the corresponding phenols 3 and 4. The assay of the glucuronides in rat urine and serum was performed by a combination of liquid/liquid extraction followed by solid phase extraction. After a high dose treatment with racemic dimethindene the diastereomeric glucuronides 5 and 6 could be directly determined in the urine of a guinea pig by CE without prior extraction or preconcentration of the urine sample. In all cases, stereoselectivities of the formation of Phase I as well as Phase II metabolites were observed.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Münster, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Rudolf
authors.forename: G
authors.initials: G
authors.lastname: Blaschke
mesh_terms: D000818:Animals; D004115:Dimethindene / Q000031:analogs & derivatives / Q000097:blood*; D019075:Electrophoresis, Capillary / Q000379:methods*; D005966:Glucuronidase / Q000378:metabolism; D020719:Glucuronides / Q000097:blood; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000097:blood*; D006801:Humans; D008968:Molecular Conformation; D015394:Molecular Structure; D051381:Rats; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D020719:Glucuronides; D006634:Histamine H1 Antagonists; D004115:Dimethindene; D005966:Glucuronidase