REGIOSELECTIVITY AND ENANTIOSELECTIVITY OF METOPROLOL OXIDATION BY 2 VARIANTS OF CDNA-EXPRESSED P4502D6

Purpose. The oxidative metabolism of metoprolol was investigated in tw o human lymphoblastoma cell-lines transfected with variants of cDNA fo r cytochrome P4502D6. Methods. The regioselective and enantioselective features of the oxidations of deuterium-labeled pseudoracemic metopro lol were characterized by GC/MS analysis of the substrate and products . Results. There were significant differences between the two P4502D6 variants in the formation kinetics of O-demethylnetoprolol and alpha-h ydroxymetoprolol. The h2D6-Val microsomes highly favored the formation of the O-demethylmetoprotol regioisomer 6.3:1 and 2.8:1, respectively from (R)-metoprolol-d(0) and (S)-metoprolol-d(2), while the correspon ding ratios for h2D6v2 microsomes were much lower. For both variants, O-demethylmetoprolol formation favored the (R)-substrate 1.5 to 2-fold , while alpha-hydroxymetoprolol formation was non-enantioselective. Si milar Km values of metoprolol oxidation, 10-20 mu M, were observed for the two microsomal preparations. Conclusions. The regioselectivity, e nantioselectivity, and Km values for the h2D6-Val microsomes resemble those observed for the native P4502D6 in human liver microsomes, where as the h2D6v2 microsomes deviated remarkably in regioselectivity.