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 were investigated in rat liver microsomal fractions. The enantiomers of primary metabolites of propranolol, 4-, 5-, 7-hydroxy- and N-desisopropyl-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 for N-desisopropylation) was observed in the formation of propranolol metabolites when the individual enantiomers or a racemic mixture of propranolol were used as substrates. Concentration-dependent metabolic inhibition of propranolol enantiomers by their optical isomers was also observed. In addition, the inhibition of propranolol 4-, 5- and 7-hydroxylations between the enantiomers showed a typical competitive nature. These findings suggested that the propranolol enantiomers competed for the same enzyme, probably a cytochrome P450 isozyme in the CYP2D subfamily.