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

John F. Bowyer, John F. Young, William Slikker, Yossef Itzak, A. J. Mayorga, Glenn D. Newport, Syed F. Ali, David L. Frederick, Merle G. Paule

Research output: Contribution to journalArticle

34 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)379-390
Number of pages12
JournalNeurotoxicology
Volume24
Issue number3
DOIs
StatePublished - Jun 2003

Keywords

  • Behavior and neurotoxicity
  • Ecstasy
  • Fenfluramine
  • Methylenedioxymethamphetamine
  • Pharmacokinetics
  • Primates

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

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