SUBSTRATE STEREOSELECTIVITY AND ENANTIOMER ENANTIOMER INTERACTION IN PROPRANOLOL METABOLISM IN RAT-LIVER MICROSOMES

The substrate stereoselectivity and enantiomer/enantiomer interaction of (S)- and (R)-propranolol for the formation of their metabolites wer e investigated in rat liver microsomal fractions. The enantiomers of p rimary metabolites of propranolol, 4-, 5-, 7-hydroxy- and N-desisoprop yl-propranolol were separated and assayed by an HPLC method employing a chiral ovomucoid column. Regioselective substrate stereoselectivity (R < S for 4- and 5-hydroxylations; R > S for 7-hydroxylation; R = S f or N-desisopropylation) was observed in the formation of propranolol m etabolites when the individual enantiomers or a racemic mixture of pro pranolol were used as substrates. Concentration-dependent metabolic in hibition of propranolol enantiomers by their optical isomers was also observed. In addition, the inhibition of propranolol 4-, 5- and 7-hydr oxylations between the enantiomers showed a typical competitive nature . These findings suggested that the propranolol enantiomers competed f or the same enzyme, probably a cytochrome P450 isozyme in the CYP2D su bfamily.