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 language | English |
|---|---|
| Pages (from-to) | 573-584 |
| Number of pages | 12 |
| Journal | Xenobiotica |
| Volume | 18 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 1988 |
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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 journal › Article
}
TY - JOUR
T1 - Disposition of ( - fenfluramine and its active metabolite, ( - norfenfluramine in rat
T2 - A single dose-proportionality study
AU - Spinelli, R.
AU - Fracasso, C.
AU - Guiso, G.
AU - Garattini, S.
AU - Caccia, S.
PY - 1988
Y1 - 1988
N2 - 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.
AB - 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.
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U2 - 10.3109/00498258809041694
DO - 10.3109/00498258809041694
M3 - Article
C2 - 3400275
AN - SCOPUS:0023908764
VL - 18
SP - 573
EP - 584
JO - Xenobiotica
JF - Xenobiotica
SN - 0049-8254
IS - 5
ER -