Studies on drug metabolism. 13. Possible role of liver microsomal cytochrome P-450 in the oxidative N-demethylation of p-substituted dimethylaniline, N-methyl-N-alkylaniline and N-methyl-N-acylaniline derivatives.

Abstract

N-Demethylation of ρ-substituted dimethylaniline derivatives, N-methyl-N-alkylaniline derivatives and N-methyl-N-acylaniline derivatives was investigated. The rates of N-demethylation of several series of ρ-substituted dimethylaniline depended upon their lipid solubilities. The more lipid soluble the amine was, the more readily it was demethylated. The ρ-substituted dimethylanilines of high lipid solubilities revealed small Km and Ks values, whereas those of low lipid solubilities exhibited large Km and Ks values. N-Demethylation activity of the high lipid soluble ρ-substituted dimethylaniline was intensely stimulated by phenobarbital administration in comparison with that of the low lipid soluble p-substituted dimethylaniline. N-Demethylation of ρ-substituted dimethylaniline of low lipid solubility was inhibited more strongly than that of high lipid solubility by SKF 525-A, but this relation between lipid solubility and inhibitory rate was not observed in carbon monoxide inhibition. The studies on N-demethylation of N-methyl-N-alkylaniline derivatives revealed that the rate of N-demethylation did not always depend on the lipid solubilities of amines. It was suggested that steric hindrance about the nitrogen atom interfered with N-demethylation of N-methyl-N-alkylaniline derivatives. In the studies on N-demethylation of N-methyl-N-acylaniline derivatives, the difference of N-demethylation rate between N-methyl-N-propyonylaniline and N-methyl-N-benzoylaniline seemed to depend on the spectral change per P-450 rather than lipid solubility.