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

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.