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N-dealkylation of propranolol in rat, dog, and man. Chemical and stereochemical aspects.

Chemical and stereochemical aspects of the metabolic N-dealkylation pathway of propranolol were examined in rat, dog, and man. Metabolites arising from pseudoracemates of propranolol were analyzed by GC-MS. In the presence of the rat liver 9000g supernatant fraction, desisopropylpropranolol arose primarily from R-propranolol while subsequent metabolites of this pathway were formed preferentially from S-propranolol. Small amounts of these metabolites (less than 3% of a 20 mg/kg ip dose) were also found as urinary metabolites in the rat. The formation of the two acidic metabolites, naphthoxylactic acid (NLA) and naphthoxyacetic acid, was stereoselective from S- and from R-propranolol, respectively. The stereochemical results from NLA formation in man in vivo were similar to those in rats, being stereoselective for S-propranolol. However, in dog administered pseudoracemic propranolol by iv infusion, more R-than S-propranolol was converted to NLA. In all experiments, in vitro (rat liver 9000g supernatant fraction) and in vivo (rat, dog, and man), the naphthoxyacetic acid formed arose preferentially from R-propranolol, when compared to the stereochemical origin of NLA. In vitro metabolism of the enantiomers of NLA also yielded significantly more naphthoxyacetic acid from the S-enantiomer of NLA (stereochemically related to R-propranolol). These results are consistent with a stereoselective conversion of S-NLA to naphthoxyacetic acid, possibly via enzymes similar to L-lactate dehydrogenase.