title: Disposition of D-fenfluramine in lean and obese rats.
abstract: The anorectic drug D-fenfluramine (D-F) was administered as single i.v. doses of 1.25 and 6.25 mg/kg to lean female Sprague-Dawley and lean and obese female Zucker rats. Blood samples were collected serially and analysed by electron capture gas-liquid chromatography for D-F and its main metabolite, D-norfenfluramine (D-NF). At the lowest dose the disappearance of D-F followed an apparent first-order process with mean elimination half-life (T1/2) of approximately 2 h in female Sprague-Dawley and 4 h in lean and obese Zucker rats. Mean absolute steady-state volume of distribution (Vss) was the same in the lean female of both strains but total clearance (Cl) was significantly lower in the Zucker rats. Therefore elimination T1/2 of D-F was longer in female Zucker than Sprague-Dawley animals. Obese rats presented lower relative Cl and Vss but no change in absolute Cl and Vss and elimination T1/2 of the drug. Intra- and inter-strain differences were observed in hepatic microsomal protein and P-450 content. As in the case of D-F the elimination T1/2 of D-NF was also longer in Zucker than Sprague-Dawley rats. No differences were observed between lean and obese rats but in all cases the elimination T1/2 of the metabolite was much longer than that of its parent drug. After larger doses (6.25 mg/kg) the kinetics of the drug were not linear. The apparent Cl declined changing the metabolite-to-parent drug ratios in all types of rats, but more evidently in Zucker than Sprague-Dawley rats and in obese than lean animals. Inter- and intra-strain differences in D-F and D-NF kinetics should be considered in neurochemical studies of the drug and extrapolation of data across animal species requires consideration of dose dependence in the rat.
authors: Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors: C
authors: C
authors: Fracasso
authors: G
authors: G
authors: Guiso
authors: S
authors: S
authors: Garattini
authors: S
authors: S
authors: Caccia
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D005260:Female; D005277:Fenfluramine / Q000378:metabolism*; D006207:Half-Life; D007700:Kinetics; D008862:Microsomes, Liver / Q000032:analysis; D009642:Norfenfluramine / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D011506:Proteins / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains / Q000378:metabolism*; D011922:Rats, Mutant Strains / Q000378:metabolism*; D011924:Rats, Zucker / Q000378:metabolism*
chemical_list: D011506:Proteins; D009642:Norfenfluramine; D005277:Fenfluramine; D003577:Cytochrome P-450 Enzyme System