N-dealkylation of tertiary amides by cytochrome P-450.
1. N-Methyl-N-alkyl-p-chlorobenzamides (alkyl = Me, Et, nPr, nBu, PhCH2, isoPr and cylcoPr) underwent mono-N-dealkylation exclusively with phenobarbital-induced rat liver microsomes; with each compound both demethylation and dealkylation occurred. 2. The time-courses showed bilinear kinetics, but there was no evidence for general suicide-substrate activity with the cyclopropyl amide, and product ratios did not vary with time. 3. The demethylation/dealkylation ratio varied from 0.3 to 2.0 among the primary alkyl groups but was ca. 40 when the alkyl group was isoPr or cylcoPr. Dealkylation of the benzyl substituent was 2-3 times more favourable than for any other primary alkyl group. Despite wide variations in the demethylation/dealkylation ratios, at near-saturating concentrations of substrates the rates of total oxidation (demethylation plus dealkylation) varied little across the entire series. 4. The results of this study are consistent with a kinetic mechanism involving significant commitment to catalysis, substituent-induced metabolic switching at the product-determining step, a non-catalytic step which is partly rate-limiting in turnover, and a chemical mechanism involving H-atom abstraction as opposed to electron abstraction.
Hall
L R
LR
Department of Medicinal Chemistry, University of Kansas, Lawrence, 66045-2506.
Hanzlik
R P
RP
D000577:Amides / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003640:Dealkylation; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D000577:Amides; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital