Evidence for an arene oxide-NIH shift pathway in the metabolic conversion of propranolol to 4'-hydroxypropranolol in the rat and in man.

To determine whether the 4'-hydroxylation of propranolol occurs by an arene oxide-NIH shift process, 4'-deuteropropranolol, prepared from 4'-iodopropranolol, was subjected to in vitro metabolic experiments in the rat liver 9000 g supernatant fraction and to in vivo metabolic experiments in man. Deuterium retention in the resulting 4'-hydroxypropranolol, determined by mass spectrometry after gas- or high-pressure liquid-chromatographic separation, was 73--75%. The results are interpreted to indicate that 4'-hydroxylation of propranolol proceeds by way of an arene oxide-NIH shift process in these two metabolic systems.