title: Regiochemistry and enantioselectivity in the oxidative N-dealkylation of verapamil.
abstract: The oxidative N-dealkylation of verapamil (1), a calcium channel antagonist, was examined in the presence of rat and human liver microsomes by using GC-MS methodology and synthesized regio-isomeric standards. All three possible secondary amine metabolites, N-methyl-4-(3,4-dimethoxyphenyl)-4-cyano-5-methylhexylamine (5), norverapamil (4), and N-methyl-2-(3,4-dimethoxyphenyl)ethylamine (3), were formed as microsomal metabolites. Compound 5 and norverapamil (4) were major products. Substrate stereoselectivity for the N-dealkylation process was determined when pseudoracemic verapamil[equimolar (S)-(-)-verapamil-d6 and (R)-(+):verapamil-d0] was used as substrate. In the presence of rat liver microsomes, a slight enantiomeric preference for the metabolism of (R)-verapamil to secondary amines 3 and 5 (S/R ratio = 0.88 and 0.78, respectively) was observed. In contrast, (S)-verapamil was preferentially metabolized to norverapamil (4) and primary amine 9 (S/R ratio = 1.20 for both). The enantioselectivity for the N-dealkylation process in the presence of human liver microsomes was slight and variable (six samples). Quantitatively, the major N-dealkylation routes in both microsomal systems yielded norverapamil (4) and secondary amine 5. Greater substrate enantioselectivity was observed for the N-dealkylation process in rat liver microsomes than in human liver microsomes. In rat liver microsomal studies, two aliphatic aldehydes (2 and 6) were successfully trapped as their O-methyloximes (7 and 11, respectively) by using methoxylamine. In addition, the alcohols formed from reduction of these aldehydes were observed, due in part to a direct reduction by NADPH.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
authors.forename: W L
authors.initials: WL
authors.lastname: Nelson
authors.forename: L D
authors.initials: LD
authors.lastname: Olsen
mesh_terms: D000818:Animals; D003640:Dealkylation; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013237:Stereoisomerism; D014700:Verapamil / Q000378:metabolism*
chemical_list: D014700:Verapamil