INVESTIGATION OF THE STEREOSELECTIVE IN-VITRO METABOLISM OF THE CHIRAL ANTIASTHMATIC ANTIALLERGIC DRUG FLEZELASTINE BY HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHY AND CAPILLARY ZONE ELECTROPHORESIS/

An achiral HPLC method using a silica gel column as well as two indepe ndent chiral analytical methods by HPLC and capillary zone electrophor esis (CZE) were developed in order to investigate the in vitro metabol ism of the racemic antiasthmatic/antiallergic drug flezelastine. The c hiral HPLC analysis was performed on a Chiralpak AD column, which also allowed the simultaneous separation of the N-dephenethyl metabolite. The chiral separation by CZE was achieved by the addition of beta-cycl odextrin to the run buffer. The stereoselectivity of the in vitro biot ransformation of flezelastine was investigated using liver homogenates of different species. Depending on the species, diverse stereoselecti ve aspects were demonstrated. The determination of the enantiomeric ra tios of flezelastine and of N-dephenethylflezelastine after incubation s of racemic flezelastine with liver microsomes revealed that porcine liver microsomes showed the greatest enantioselectivity of the biotran sformation. (-)-Flezelastine was preferentially metabolized. After inc ubations with bovine liver microsomes the enantiomer of N-dephenethylf lezelastine formed from (+)-flezelastine dominated. Incubations of the pure enantiomers of flezelastine with induced rat liver microsomes re sulted in the stereoselective formation of a hitherto unknown metaboli te, which was only detected in samples of (+)-flezelastine. Initial st ructure elucidation of the compound indicated that the new metabolite was most likely an aromatically hydroxylated derivative of the N-dephe nethylflezelastine.