On the Aromatic Hydroxylation of Amphetamine in Rat Liver Microsomes and Perfused Liver Preparations: Effects of Long‐term Administration

Abstract

The liver microsomal p-hydroxylation of amphetamine to p-hydroxyamphetamine (pOHA) was dependent on NADP and inhibited by CO indicating the involvement of cytochrome P-450. SKF 525-A [2-diethylaminoethyl 2,2-diphenylvalerate hydrochloride], fenfluramine and desmethylimipramine were the most effective inhibitors of this pathway of amphetamine metabolism. Repeated administration of phenobarbital resulted in reduced p-hydroxylation of amphetamine in vitro. Chronic administration of amphetamine reduced the microsomal p-hydroxylation of amphetamine without apparent changes in the cytochrome P-450 levels or in the activity of NADPH-cytochrome c reductase. The aromatic hydroxylation of aniline and the demethylation of ethylmorphine was not affected by this treatment. The 455 nm complex formed during the microsomal metabolism of N-hydroxyamphetamine was increased by the long-term administration of amphetamine. Some pecularities of the in vitro hydroxylation of amphetamine by rat liver microsomes probably occurred. Amphetamine disappeared from the perfusate of the perfused liver at the same rate in rats given a single dose of amphetamine and in rats given amphetamine orally for 4 wk. The excretion of pOHA and its conjugate increased at 60 and 90 min, and 30, 60 and 90 min, respectively, in the perfusate of the same experiment as compared to the controls. The total excretion of radioactive amphetamine metabolites at the end of the perfusion was increased in the perfusate and reduced in the bile compared to the control experiment.