Chemical and stereochemical aspects of propranolol metabolism. Diastereomeric 1-(1-hydroxy-2-propylamino)-3-(1-naphthoxy)-2-propanols produced by rat liver microsomal ω-hydroxylation

Article abstract of DOI:10.1021/jm00160a034

A new metabolic pathway of terminal hydroxylation (ω-hydroxylation) of the N-isopropyl group of propranolol was established. Selected ion-monitoring GC-MS analysis, based on use of the synthesized mixture of diastereoisomers of 1-(1-hydroxy-2-propylamino)-3-(1-naphthoxy)-2-propanol as a standard, established formation of both diastereoisomers of 2 as metabolites of 1. These diastereoisomers were formed in unequal amounts when 1, its hexadeuterated analogue or heptadeuterated analogue were incubated in the presence of the rat liver microsomal fraction. Authentic (2R,2)-2, obtained from the amide formed from (2S)-3-(1-naphthoxy)-2-hydroxypropionic acid and (2S)-alaninol by diborane reduction, facilitated examination of stereochemical aspects of this process. From incubations of the enantiomers of 1 and pseudoracemic propranolol [equimolar (2R)-propranolol-3,3-d₂ and (2S)-propranolol-d₀] in the presence of the rat liver microsomal fraction, we established that the diastereomeric products were formed in the order (2S,2''S)-2?(2S,2''R)-2 > (2R,''R)-2 > (2R,2''S)-2. (2S)-1, which was metabolized to 2 to a greater extent than (2R)-1, showed no stereoselectivity, affording about equal amounts of (2S,2''S)-2 and (2S,2''R)-2. (2R)-1, which was metabolized to 2 to a lesser extent, afforded considerably more (2R,2''R)-2 than (2R,2''S)-2. ω-Hydroxylation was a minor metabolic pathway in the microsomal incubation. About 2000 X less 2 than 1-amino-3-(1-naphthoxy)-2-propanol, the product of N-dealkylation of 1, was formed.