Vol. 284, Issue 2, 618-624, February 1998

Fenfluramine and Norfenfluramine Levels in Brain Microdialysate, Brain Tissue and Plasma of Rats Administered Doses of d-Fenfluramine Known to Deplete 5-Hydroxytryptamine Levels in Brain

Peter Clausing¹ , Glenn D. Newport and John F. Bowyer

Division of Neurotoxicology (P.C., G.D.N., J.F.B.), National Center for Toxicological Research, Jefferson, Arkansas and Scantox Biological Laboratories (P.C.), 4623 Lille Skendsved, Denmark

The relationship between dose, frontal cortex (brain) microdialysate and brain tissue levels of fenfluramine (FEN) and norfenfluramine (NF), as well as the effect that these levels have on body temperature, was determined after systemic d-FEN. FEN and NF levels were monitored continuously in the microdialysate of adult male Sprague-Dawley rats dosed with 3 × 5 mg/kg s.c. (spaced 2 hr apart), 1 × 2 mg/kg s.c. or 1 × 10 mg/kg i.p. d-FEN (at ambient temperatures of either 23°C or 27°C). Drug concentrations in plasma and brain regions were also determined 1 hr after one or three doses of 5 mg/kg of d-FEN and 1 and 8 hr after 10 mg/kg d-FEN, and the levels of 5-hydroxytryptamine and 5-hydroxyindole acetic acid in the frontal cortex of FEN and controls were determined 4 days after dosing. Peak microdialysate FEN levels, occurring between 40 and 60 min after the first dose, were 0.24 ± 0.07 µM after 2 mg/kg, 0.33 ± 0.04 µM after 5 mg/kg and 1.65 µM after 10 mg/kg. After multiple doses of 5 mg/kg FEN the time-to-peak level was greater than 80 min with peaks of 0.68 ± 0.04 µM after the second dose and 1.20 ± 0.07 µM after the third dose. There was a positive correlation between combined (FEN + NF) peak levels in microdialysate and the increase in body temperature after 10 mg/kg d-FEN at 27°C; however, the group mean and peak levels of FEN and NF in microdialysate were statistically the same at either 23°C or 27°C. The indole-depleting effect of d-FEN at 4 days after dosing was exacerbated at 27°C when hyperthermia occurred. Thus, hyperthermia does not affect the pharmacokinetics of d-FEN but pharmacokinetics can influence the degree of hyperthermia in a 27°C environment. Plasma levels, brain extracellular and brain levels of approximately 1 µM, 2.5 µM and 50 µM FEN (respectively), or greater, result from 5-hydroxytryptamine-depleting doses of 5 mg/kg s.c. FEN.