Plasma Levels of Parent Compound and Metabolites after Doses of Either d-Fenfluramine or d-3,4-Methylenedioxymethamphetamine (MDMA) that Produce Long-Term Serotonergic Alterations
Section snippets
INTRODUCTION
d-Fenfluramine (FEN) is an anorectic previously prescribed to treat obesity until the FDA recalled it over concerns about possible peripheral toxicity (Doogan, 1982, Roche et al., 1992, Cacoub et al., 1995). In addition to the possible peripheral toxicity of FEN seen in humans, it can evoke a prolonged depletion of serotonin (5-HT) in brain regions of rats and monkeys at higher doses (Harvey and McMaster, 1975, Clineschmidt et al., 1976, Clineschmidt et al., 1978, Kleven et al., 1988, Appel et
Subjects
Nine adult male rhesus monkeys (Macaca mulatta) between 8 and 19 years of age and weighing from 7 to 10 kg served as subjects. Six animals had previously been trained to perform behavioral tasks in the NCTR operant test battery (OTB) and had done so for several years; the three control subjects had not. During the year preceding this study, one subject in the FEN group (M79) and two in the MDMA group (M81 and M436) had been exposed to cocaine and ditolyquanidine during separate studies to
RESULTS
The plasma levels for FEN and NFEN after the first and seventh (last) doses of 5 mg/kg (equivalent to 18.8 μmol/kg) FEN for each of the three monkeys given FEN are shown in Fig. 1. The average plasma levels for FEN and NFEN after the first and seventh (last) doses are shown in Fig. 2 (without the SEM bars to facilitate viewing) along with simulated levels of both compounds. Peak FEN plasma levels of 2.04±0.35 μM were reached within 40 min after the first dose, and then declined rapidly while peak
DISCUSSION
With respect to the plasma levels of FEN and NFEN seen in our studies after multiple twice daily treatments with FEN, it is apparent that our data are commensurate with what would be predicted from previous studies that also evaluated plasma levels in rhesus monkeys (Caccia et al., 1995). A single oral dose of 2 mg/kg FEN resulted in peak plasma levels of 0.061 μM (14 ng/ml) FEN and 0.451 μM (97 ng/ml) NFEN in those studies. The peak NFEN-levels reported by Caccia et al. (1995) are about the same as
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