Pathways of gallopamil metabolism. Regiochemistry and enantioselectivity of the N-dealkylation processes

Abstract

The N-dealkylation pathway for the metabolism of pseudoracemic gallopamil was studied in the presence of rat and human liver microsomes and in vivo in rats and man. Metabolites were characterized by comparison of their GC/MS retention times and fragmentation patterns with those of authentic compounds. In the presence of rat liver microsomes, N-dealkylation accounted for about 90% of the observed oxidative metabolism, affording a 4:1 ratio of norgallopamil (2) and, N-methyl-N-[2-methyl-3-cyano-3-(3,4,5-trimethoxyphenyl)-6-hexyl] amine (3), and about 1% of N-methyl-N-(3,4-dimethoxyphenethyl)amine (4). Secondary amines 2 and 3 arose enantioselectively from S-(-)-gallopamil, the S/R ratios being 1.36 and 1.71, respectively. The alcohols, 3,4-dimethoxyphenylethanol (6) and 2-methyl-3-cyano-3-(3,4,5-trimethoxyphenyl)-6-hexanol (8), were formed from the respective intermediate aldehydes 5 and 7, probably non-enzymatically, under the reductive conditions (NADPH) of the microsomal incubations. Incubation of gallopamil with 9,000g supernatant fraction of rat liver led to carboxylic acid metabolites arising from oxidative metabolism of the aldehydes. 3,4-Dimethoxyphenylacetic acid (12) and 4-(3,4,5-trimethoxyphenyl)-5-methyl-4-cyanohexanoic acid (11) were formed in a 3:5:1 ratio. In the presence of human liver microsomes, formation of 2 also predominated over formation of 3, with alcohols 6 and 8 being produced as well. However, 4 was not observed. Consistently, the N-dealkylation process provided slightly more R than S products with the S/R ratio being 0.7-0.9 for metabolites 2, 3, 6, and 8. The amines formed from N-dealkylation were also observed as urinary metabolites in a human subject after a single oral dose of pseudoracemic gallopamil.(ABSTRACT TRUNCATED AT 250 WORDS)