On the inhibition of microsomal drug metabolism by SKF 525-A

Kinetic experiments have been carried out on the inhibition of the O-demethylation of p-nitroanisole and the N-demethylation of N-monomethyl-p-nitroaniline by β-diethylaminoethyl-diphenyl-n-propylacetate-HCl (SKF 525-A). The source of the enzyme were liver microsomes of male mice pretreated with phenobarbital. Addition of original SKF 525-A to the reaction mixture resulted in an apparently non-competitive inhibition of both demethylation reactions. When the substance was recrystallized from benzene the non-competitive type of inhibition was converted to an apparent competitive type of inhibition. Use of other solvents for recrystallization such as water, methanol, cyclohexane and chlorobenzene did not lead to a change of the type of inhibition. Therefore recrystallization from benzene seemed to be unique in causing this peculiar change of kinetic behaviour. Benzene produces no chemical alteration of the SKF 525-A molecule that could be detected by a number of physicochemical methods employed.