FENFLURAMINE AND NORFENFLURAMINE LEVELS IN BRAIN MICRODIALYSATE, BRAIN-TISSUE AND PLASMA OF RATS ADMINISTERED DOSE OF D-FENFLURAMINE KNOWN TO DEPLETE 5-HYDROXYTRYPTAMINE LEVELS IN BRAIN

The relationship between dose, frontal cortex (brain) microdialysate a nd 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. FEP and NF levels were monitored con tinuously in the microdialysate of adult male Sprague-Dawley rats dose d with 3 x 5 mg/kg s.c. (spaced 2 hr apart), 1 x 2 mg/kg s.c. or 1 x 1 0 mg/kg i.p. d-FEN (at ambient temperatures of either 23 degrees C or 27 degrees C). Drug concentrations In plasma and brain regions were al so 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 a nd 5-hydroxyindole acetic acid in the frontal cortex of FEN and contro ls 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 mu M after 2 mg/kg, 0.33 +/- 0.04 mu M after 5 mg/kg and 1.65 mu M 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 mu M after t he second dose and 1.20 +/- 0.07 mu M after the third dose. There was a positive correlation between combined (FEN + NF) peak levels in micr odialysate and the increase in body temperature after 10 mg/kg d-FEN a t 27 degrees C; however, the group mean and peak levels of FEN and NF in microdialysate were statistically the same at either 23 degrees C o r 27 degrees C. The indole-depleting effect of d-FEN at 4 days after d osing was exacerbated at 27 degrees C when hyperthermia occurred. Thus , hyperthermia does not affect the pharmacokinetics of d-FEN but pharm acokinetics can influence the degree of hyperthermia in a 27 degrees C environment, Plasma levels, brain extracellular and brain levels of a pproximately 1 mu M, 2.5 mu M and 50 mu M FEN (respectively), or great er, result from 5-hydroxytryptamine-depleting doses of 5 mg/kg s.c. FE N.