METABOLISM OF DIMETINDENE IN RATS

The preparative separation of dimetindene (CAS 5636-83-9) enantiomers was achieved by fractionated crystallization of the diastereomeric tar trate salts. HPLC on alpha-AGP (alpha(1)-acid glycoprotein) was used f or confirmation of the enantiomeric purity. After administration of th e enantiomers to rats the AUC and C-max of S(+)dimetindene and (-)N-de methyldimetindene were slightly increased. In agreement with the serum concentration data significantly more (-)N-demethyldimetindene was ex creted into urine after administration of the individual enantiomers. S(+)dimetindene was metabolised to a lesser extent in vivo (see above) as well as in vitro in rat liver homogenate. After prior enzyme induc tion conversion of the enantioselectivity with respect to unmetabolise d dimetindene occurred. 6-Methoxydimetindene, 6-hydroxydimetindene and 6-hydroxy-N-demethyldimetindene were synthesized. 6-Methoxydimetinden e is likely to be a metabolite since the retention times of synthetic compound and the substance extracted from serum and urine are identica l. The formation of 6-hydroxy-N-demethyldimetinedene was proved for th e first time by comparison of the mass spectra of metabolite isolated from in vitro incubations and synthetic compound after derivatisation with acetic anhydride.