title: 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.
abstract: Plasma levels of parent compounds and metabolites were determined in adult rhesus monkeys after doses of either 5mg/kg d-fenfluramine (FEN) or 10mg/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 microM FEN were reached within 40min after the first dose of FEN, and then declined rapidly, while peak plasma levels (0.4+/-0.1 microM) of the metabolite norfenfluramine (NFEN) were not reached until 6h 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 t(1/2) for FEN was 2.6+/-0.3h after the first dose and 3.2+/-0.2h after the seventh. The estimated t(1/2) for NFEN was more than 37.6+/-20.5h. Peak plasma levels of 9.5+/-2.5 microM MDMA were reached within 20min after the first dose of MDMA, and then declined rapidly, while peak plasma levels (0.9+/-0.2 microM) of the metabolite 3,4-methylenedioxyamphetamine (MDA) were not reached until 3-6h 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 t(1/2) for MDMA was 2.8+/-0.4h after the first and 3.9+/-1.1h after the seventh dose. The estimated t(1/2) for MDA was about 8.3+/-1.0h. 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.
authors.affiliation: Division of Neurotoxicology and Biometry and Risk Assessment, National Center for Toxicological Research/FDA, 72079-9502, Jefferson, AR, USA. jbowyer@nctr.fda.gov
authors.forename: John F
authors.initials: JF
authors.lastname: Bowyer
authors.forename: John F
authors.initials: JF
authors.lastname: Young
authors.forename: William
authors.initials: W
authors.lastname: Slikker
authors.forename: Yossef
authors.initials: Y
authors.lastname: Itzak
authors.forename: A J
authors.initials: AJ
authors.lastname: Mayorga
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Newport
authors.forename: Syed F
authors.initials: SF
authors.lastname: Ali
authors.forename: David L
authors.initials: DL
authors.lastname: Frederick
authors.forename: Merle G
authors.initials: MG
authors.lastname: Paule
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000097:blood / Q000378:metabolism; D005277:Fenfluramine / Q000008:administration & dosage* / Q000097:blood / Q000378:metabolism*; D008253:Macaca mulatta; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood / Q000378:metabolism; D026901:Membrane Transport Proteins; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000008:administration & dosage* / Q000097:blood / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D012701:Serotonin / Q000097:blood / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins; D013995:Time
chemical_list: D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D005277:Fenfluramine; D012701:Serotonin; D018817:N-Methyl-3,4-methylenedioxyamphetamine