Elsevier

NeuroToxicology

Volume 24, Issue 3, June 2003, Pages 379-390
NeuroToxicology

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

https://doi.org/10.1016/S0161-813X(03)00030-5Get rights and content

Abstract

Plasma levels of parent compounds and metabolites were determined in adult rhesus monkeys after doses of either 5 mg/kg d-fenfluramine (FEN) or 10 mg/kg d-3, 4-methylenedioxymethamphetamine (MDMA) i.m. twice daily for four consecutive days. These treatment regimens have been previously shown to produce long-term serotonin (5-HT) depletions. Peak plasma levels of 2.0±0.4 μM FEN were reached within 40 min after the first dose of FEN, and then declined rapidly, while peak plasma levels (0.4±0.1 μM) of the metabolite norfenfluramine (NFEN) were not reached until 6 h after dosing. After the seventh (next to last) dose of FEN, peak plasma levels of FEN were 35% greater than after the first dose while peak NFEN-levels were 500% greater. The t1/2 for FEN was 2.6±0.3 h after the first dose and 3.2±0.2 h after the seventh. The estimated t1/2 for NFEN was more than 37.6±20.5 h. Peak plasma levels of 9.5±2.5 μM MDMA were reached within 20 min after the first dose of MDMA, and then declined rapidly, while peak plasma levels (0.9±0.2 μM) of the metabolite 3,4-methylenedioxyamphetamine (MDA) were not reached until 3–6 h after dosing. After the seventh (next to last) dose of MDMA, peak plasma levels of MDMA were 30% greater than the first dose while peak MDA levels were elevated over 200%. The t1/2 for MDMA was 2.8±0.4 h after the first and 3.9±1.1 h after the seventh dose. The estimated t1/2 for MDA was about 8.3±1.0 h. Variability in plasma levels of MDMA and MDA between subjects was much greater than that for FEN and NFEN. This variability in MDMA and MDA exposure levels may have lead to variability in the subsequent disruption of some behaviors seen in these same subjects. There were 80% reductions in the plasma membrane-associated 5-HT transporters 6 months after either the FEN or MDMA dosing regimen indicating that both treatments produced long-term serotonergic effects.

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

References (59)

  • J.E. Malberg et al.

    Administration of fenfluramine at different ambient temperatures produces different core temperature and 5-HT neurotoxicity profiles

    Brain Res.

    (1997)
  • U.D. McCann et al.

    Positron emission tomography evidence of toxic effect of MDMA (“ecstasy”) on brain serotonin neurons in human beings

    Lancet

    (1998)
  • D.C. Molliver et al.

    Anatomic evidence for a neurotoxic effect of (+)-fenfluramine upon serotonergic projections in the rat

    Brain Res.

    (1990)
  • K.A. Moore et al.

    Distribution of 3,4-methylenedioxymethamphetamine (MDMA) and methylenedioxyamphetamine (MDA) stereoisomers in a fatal poisoning

    Forensic Sci. Int.

    (1996)
  • M.G. Paule

    Use of the NCTR operant test battery in nonhuman primates

    Neurotoxicol. Teratol.

    (1990)
  • G.A. Ricaurte et al.

    Dexfenfluramine neurotoxicity in brains of non-human primates

    Lancet

    (1991)
  • W. Slikker et al.

    Neurochemical and neurohistological alterations in the rat and monkey produced by orally administered methylenedioxymethamphetamine (MDMA)

    Toxicol. Appl. Pharmacol.

    (1988)
  • N.M. Appel et al.

    Fenfluramine selectively and differentially decreases the density of serotonergic nerve terminals in rat brain: evidence from immunocytochemical studies

    J. Pharmacol. Exp. Ther.

    (1989)
  • H.W. Broening et al.

    Age-dependent sensitivity of rats to the long-term effects of the serotonergic neurotoxicant (+)-3,4-methylenedioxymethamphetamine (MDMA) correlates with the magnitude of MDMA-induced hyperthermia

    J. Pharmacol. Exp. Ther.

    (1995)
  • C. Brown et al.

    Multiple severe complications from recreational ingestion of MDMA (“ecstasy”)

    JAMA

    (1987)
  • R.W. Byard et al.

    Amphetamine derivative fatalities in South Australia—is “ecstasy” the culprit?

    Am. J. Forensic Med. Pathol.

    (1998)
  • S. Caccia et al.

    Oral kinetics of dexfenfluramine and dexnorfenfluramine in non-human primates

    Xenobiotica

    (1995)
  • P. Cacoub et al.

    Pulmonary hypertension and dexfenfluramine

    Eur. J. Clin. Pharmacol.

    (1995)
  • D.B. Campbell

    The use of toxicokinetics for the safety assessment of drugs acting in the brain

    Mol. Neurobiol.

    (1995)
  • G. Cheymol et al.

    The pharmacokinetics of dexfenfluramine in obese and non-obese subjects

    Br. J. Clin. Pharmacol.

    (1995)
  • G. Cimbura

    3,4-Methylenedioxyamphetamine (MDA): analytical and forensic aspects of fatal poisoning

    J. Forensic Sci.

    (1972)
  • P. Clausing et al.

    d-Fenfluramine and norfenfluramine levels in brain microdialysate

    J. Pharmacol. Exp. Ther.

    (1998)
  • B.V. Clineschmidt et al.

    Fenfluramine and brain serotonin

    Ann. N. Y. Acad. Sci.

    (1978)
  • D.P. Doogan

    Pulmonary hypertension and fenfluramine

    Br. Med. J. Clin. Res. Ed.

    (1982)
  • Cited by (0)

    View full text