Single- and multiple-dose kinetics of d-fenfluramine in rats given anorectic and toxic doses

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

Research output: Contribution to journalArticle

Abstract

1. High parenteral doses of a twice-daily schedule of d,l-fenfluramine (d,l,-F) may cause long-lasting decrease of functional indices of brain serotoninergic neurones in rats. The single- and multiple-dose (b.i.d. x 4 days) kinetics of low (1.25 mg/kg) and high (12.5 mg/kg) subcutaneous (s.c.) doses of d-F, which accounts of the anorectic effects of the racemate, and its deethylated metabolite d-norfenfluramine (d-NF), were therefore examined and compared with those of pharmacologically effective oral doses (0.3-1.25 mg/kg) in rats. 2. There were dose-dependent alterations of kinetic parameters after s.c. and oral dosing, indicating that hepatic clearance of d-F in the rat can be saturated either by increasing the size of the single dose or during repeated dosing. Nonlinearity was also observed for d-NF. Consequently at high doses exposure of rat to the drug, as measured by the sum of area under the plasma concentration-time curve (AUC) of d-F and d-NF considerably exceeded that expected from simple dosage considerations, particularly with repeated administration of d-F. 3. Total exposure at the high doses considerably exceeded that at pharmacological doses, however, indicating an ample margin in favour of anorectic activity. The possibility that the long-term depletion of brain 5-HT by d-F and/or its metabolite d-NF may have relevance at the usual therapeutic dose, is discussed.

Original languageEnglish
Pages (from-to)217-226
Number of pages10
JournalXenobiotica
Volume22
Issue number2
DOIs
Publication statusPublished - 1992

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Norfenfluramine
Fenfluramine
Appetite Depressants
Poisons
Rats
Kinetics
Metabolites
Brain
Serotonergic Neurons
Kinetic parameters
Neurons
Area Under Curve
Serotonin
Appointments and Schedules
Pharmacology
Plasmas
Liver
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology
  • Biochemistry
  • Health, Toxicology and Mutagenesis
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Single- and multiple-dose kinetics of d-fenfluramine in rats given anorectic and toxic doses. / Caccia, S.; Anelli, M.; Ferrarese, A.; Fracasso, C.; Garattini, S.

In: Xenobiotica, Vol. 22, No. 2, 1992, p. 217-226.

Research output: Contribution to journalArticle

Caccia, S. ; Anelli, M. ; Ferrarese, A. ; Fracasso, C. ; Garattini, S. / Single- and multiple-dose kinetics of d-fenfluramine in rats given anorectic and toxic doses. In: Xenobiotica. 1992 ; Vol. 22, No. 2. pp. 217-226.
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