Effect of d-fenfluramine on the indole contents of the rat brain after treatment with different inducers of cytochrome P450 isoenzymes

M. Anelli, C. Fracasso, A. Bergami, A. Ferrarese, S. Garattini, S. Caccia

Research output: Contribution to journalArticle

Abstract

The effects of pretreatment with inducers of hepatic cytochrome P450 isoenzymes (phenobarbital, dexamethasone and β-naphthoflavone) on the metabolism of d-fenfluramine (d-F) and its acute and long-lasting indole-depleting effects were studied in rats, in an effort to obtain further information on the importance of hepatic drug metabolism in relation to its neurochemical actions. Twenty-four hours after the last dose of each inducer, rats were injected with d-F hydrochloride (5 mg/kg, IP) and killed at various times thereafter for parallel determination of indoles and drug concentrations in plasma and brain. Additional rats were treated as above and killed 1 week after d-F hydrochloride (5 and 10 mg/kg) to study the recovery of indole in the cortex, a particularly sensitive brain area. Phenobarbital and β-naphthoflavone and, to a lesser degree, dexamethasone, stimulated the metabolism of d-F, as evidenced by a decrease in plasma and brain areas under the curve (AUC) compared to vehicle-treated rats. This indicated that multiple isoenzymes are capable of mediating the drug's metabolism, primarily by N-dealkylation to d-norfenfluramine (d-NF). None of the inducers raised plasma and brain AUC of the nor-derivative, and in fact phenobarbital and particularly β-naphthoflavone reduced it. These different effects were even apparent in rats given d-NF (2.5 mg/kg), indicating that both phenobarbital and β-naphthoflavone also stimulate the sequential metabolism of the nor-metabolite (by N-deamintaion) which, however, is apparently enhanced most actively by β-naphthoflavone-inducible forms of P-450. Total "active" brain concentrations (d-F+d-NF) after the different pretreatments were in the order of β-naphthoflavone <phenobarbital <dexamethasone ≤ vehicle. Interestingly, β-naphthoflavone rapidly reversed the depletion of brain indoles caused by d-F (and d-NF); phenobarbital provided partial protection and dexamethasone did not appreciably modify either the acute or long-term neurochemical effects of the drug. The fact that phenobarbital affected d-NF kinetics less than β-naphthoflavone, and provided only partial protection against the acute and long-lasting neurochemical effects of high doses of d-F, further stresses the critical role of d-NF in the neurochemical outcome of its parent drug. These findings support the view that the degree and duration of the indole-depleting effects are related to critical brain concentrations of the parent compound and its nor-derivative, and provide indirect evidence that hepatic metabolites other than d-NF are unlikely to play any role in the neurochemical effects of high doses of d-F in rats.

Original languageEnglish
Pages (from-to)188-194
Number of pages7
JournalPsychopharmacology
Volume118
Issue number2
DOIs
Publication statusPublished - Mar 1995

Keywords

  • Brain kinetics
  • d-Fenfluramine
  • Indole-depleting effect
  • Inducers of drug metabolism
  • Rat

ASJC Scopus subject areas

  • Pharmacology

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