Disposition of (-)-fenfluramine and its active metabolite, (-)-norfenfluramine in rat: a single dose-proportionality...

1. The disposition of (-)-fenfluramine, (-)-F, was studied in rats after i.v. and oral administration (1.25 to 12.5 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 6.25 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 (12.5 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.