Single- and multiple-dose kinetics of d-fenfluramine in rats given anorectic and toxic doses.
1. High parenteral doses of a twice-daily schedule of d,l-fenfluramine (d,l-F) may cause long-lasting decrease of functional indices of brain serotoninergic neurones in rats. The single- and multiple-dose (b.i.d. x 4 days) kinetics of low (1.25 mg/kg) and high (12.5 mg/kg) subcutaneous (s.c.) doses of d-F, which accounts of the anorectic effects of the racemate, and its deethylated metabolite d-norfenfluramine (d-NF), were therefore examined and compared with those of pharmacologically effective oral doses (0.3-1.25 mg/kg) in rats. 2. There were dose-dependent alterations of kinetic parameters after s.c. and oral dosing, indicating that hepatic clearance of d-F in the rat can be saturated either by increasing the size of the single dose or during repeated dosing. Nonlinearity was also observed for d-NF. Consequently at high doses exposure of rat to the drug, as measured by the sum of area under the plasma concentration-time curve (AUC) of d-F and d-NF considerably exceeded that expected from simple dosage considerations, particularly with repeated administration of d-F. 3. Total exposure at the high doses considerably exceeded that at pharmacological doses, however, indicating an ample margin in favour of anorectic activity. The possibility that the long-term depletion of brain 5-HT by d-F and/or its metabolite d-NF may have relevance at the usual therapeutic dose, is discussed.
Caccia
S
S
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Anelli
M
M
Ferrarese
A
A
Fracasso
C
C
Garattini
S
S
D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005277:Fenfluramine / Q000493:pharmacokinetics* / Q000633:toxicity; D007279:Injections, Subcutaneous; D008297:Male; D009642:Norfenfluramine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D009642:Norfenfluramine; D005277:Fenfluramine