Stereoselectivity of the Phase-II-metabolism of the H-1 antihistaminic drug dimethindene investigated by capillary electrophoresis

Two capillary electrophoretic (CE) methods for the determination of conjuga ted metabolites of the antihistaminic drug dimethindene were developed. The se methods allow the determination of the diastereomeric ratios of both Pha se II glucuronides, 6-hydroxy dimethindene glucuronide (5) and 6-hydrosy-N- demethyl dimethindene glucuronide (6). Furthermore, after enzymatic deconju gation 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 spec trometry and deconjugation with 1-glucuronidase to the corresponding phenol s 3 and 4. The assay of the glucuronides in rat urine and serum was perform ed by a combination of liquid/liquid extraction followed by solid phase ext raction. After a high dose treatment with racemic dimethindene the diastere omeric glucuronides 5 and 6 could be directly determined in the urine of a guinea pig by CE without Frier extraction or preconcentration of the urine sample. In all cases, stereoselectivities of the formation of Phase I as we ll as Phase II metabolites were observed.