Disposition of ( - fenfluramine and its active metabolite, ( - norfenfluramine in rat: A single dose-proportionality study

R. Spinelli, C. Fracasso, G. Guiso, S. Garattini, S. Caccia

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Abstract

1. The disposition of ( - fenfluramine, ( - F, was studied in rats after i.v. and oral administration (1̇25 to 12̇5 mg/kg). Whole blood-to-plasma ratio and the protein binding (determined by equilibrium dialysis) of the compound and its main active metabolite, ( - norfenfluramine ( - NF, were investigated. 2. The bound fraction of both compounds (about 40% was constant in the concentration range of 1-10 nmol/ml. The whole blood to plasma concentration ratios of ( - F and ( - NF were larger than unity and were constant over this dose range. 3. The drug followed apparent first-order kinetics, at doses up to 6̇25 mg/kg. The mean half-lives of the parent drug and its metabolite were about 1 and 12 h respectively. The volume of distribution of ( - F was large and total body clearance approached liver blood flow. 4. Oral doses were rapidly absorbed from the rat gastrointestinal tract. Bioavailability of the drug was about 20% Urinary excretion of unchanged drug (3-4% of dose) and its metabolite (about 20% were similar after i.v. and oral administration. 5. After larger doses (12̇5 mg/kg) the kinetics of ( - F were nonlinear. The AUC increased, but not in proportion to the dose, and kinetic parameters were modified. 6. Brain concentrations reflected the dose-related changes observed in ( - F and ( - NF blood concentrations, and patterns of brain distribution and subcellular localization of the drug and its metabolite were modified at the highest dose tested.

Original languageEnglish
Pages (from-to)573-584
Number of pages12
JournalXenobiotica
Volume18
Issue number5
DOIs
Publication statusPublished - 1988

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Norfenfluramine
Fenfluramine
Metabolites
Rats
Blood
Pharmaceutical Preparations
Oral Administration
Brain
Plasmas
Kinetics
Dialysis
Kinetic parameters
Protein Binding
Liver
Biological Availability
Area Under Curve
Gastrointestinal Tract
Blood Proteins

ASJC Scopus subject areas

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

Cite this

Disposition of ( - fenfluramine and its active metabolite, ( - norfenfluramine in rat : A single dose-proportionality study. / Spinelli, R.; Fracasso, C.; Guiso, G.; Garattini, S.; Caccia, S.

In: Xenobiotica, Vol. 18, No. 5, 1988, p. 573-584.

Research output: Contribution to journalArticle

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