Abstract

The chronic administration (5 days) of SKF 525-A and Lilly 18947 to rats induced increased microsomal enzyme activity as measured by the N-dealkylation of these compounds themselves as well as that of ethylmorphine. In rats whose rates of hexobarbital metabolism had been increased as a result of the repeated administration of SKF 525-A, hexobarbital metabolism was still inhibited when a final dose of SKF 525-A was given. Similarly, in phenobarbital treated rats, SKF 525-A, its product of N-dealkylation, 2-ethylaminoethyl 2,2-diphenylvalerate HCl (SKF 8742-A), and its primary amine analog, 2-aminoethyl 2,2-diphenylvalerate HBr (AEDV), were all effective inhibitors of the enhanced rate of hexobarbital metabolism. These results are explained on the basis that the inductive process involves the synthesis of new enzymic protein that is as readily inhibited by SKF 525-A type compounds as that which was present before induction. Even though the rate of metabolism of SKF 525-A is increased as a result of induction it continues to exert its effects through its products of N-dealkylation, which are also excellent inhibitors.