In vivo and in vitro Inhibition of the Metabolism of N-Alkyl-substituted Amphetamines in Rat by Ferrocenylisopropylamine

Abstract

1. Ferrocenylisopropylamine (FIPA) inhibits the elimination of amphetamines in rat. The half-life of isopropylamphetamine was increased from approx. 30 to 85–100 min after administration of FIPA.

2. With isolated, perfused, rat liver, the half-lives of isopropylamphetamine, biamphetamine and benzylamphetamine were increased from 5–20 min to about 200 min by equimolar amounts of FIPA, indicating that the prolonging effect of FIPA is due to interference at the metabolic level.

3. Experiments with hepatic microsomal suspensions demonstrated that FIPA competitively inhibits the oxidative N-dealkylation of isopropylamphetamine; the K_i of FIPA is 4·1 × 10^?6 M.

4. Binding of isopropylamphetamine and FIPA to cytochrome P-450 was studied using hepatic microsomes of phenobarbital-treated rats. Isopropylamphetamine caused a type I, and FIPA a type II difference spectrum; FIPA showed a much higher binding affinity (K_s = 1·24 × 10^?2 M) than isopropylarnphetamine (K_s = 0·96 × 10^?3 M). FIPA acts as a modifier of the spectral changes induced by isopropylamphetamine.

5. Results suggest that the competitive inhibition of the N-dealkylation of N-alkylamphetamines, and thus the prolonging of their action, by FIPA is related to competition for binding to cytochrome P-450.