N-Dealkylation of tertiary amides by cytochrome P-450

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Abstract
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.