Interactions of perhexiline maleate and arylalkylamine derivatives with cytochrome P-450 and in-vitro hydroxylation

Abstract

In order to find a substitute for perhexiline maleate, an antiangor drug, for which several side effects due to poor hydroxylation have been reported, an arylalkylamine series with antianginal properties has been synthesized. The aim of the present work was to select a more rapidly hydroxylated compound than perhexiline maleate in this series. Two criteria have been retained. The binding of the molecules to liver microsomal cytochrome P-450 and their rate of hydroxylation were both studied in vitro using phenobarbital induced rat liver microsomes. Incubation with cofactors and extraction procedures have been tested on one of the molecules of the series taken as example: N-2-dicyclohexyl2-phenethylamine (3). All of the molecules tested in the series substrates were type I substrates; nevertheless, no correlation was found between binding on cytochrome P-450 and oxydative metabolism of the drugs. Two of the studied molecules were more easily hydroxylated than the others and than perhexiline maleate: (3) ( N-dicyclohexyl-phenethylamine) and (II) ( N-cyclohexyl-2-diphenylethylamine) with the following respective kinetics: Apparent V max: 0.073 and 0.32 units, apparent K m: 6.9 × 10 −5 M and 22.2 × 10 −5 M.