title: (±)-3,4-methylenedioxymethamphetamine and metabolite disposition in plasma and striatum of wild-type and multidrug resistance protein 1a knock-out mice.
abstract: Mice lacking multidrug resistance protein 1a (mdr1a) are protected from methylenedioxymethamphetamine (MDMA)-induced neurotoxicity, suggesting mdr1a might play an important role in this phenomenon. We characterized MDMA pharmacokinetics in murine plasma and brain to determine if mdr1a alters MDMA distribution. Wild-type (mdr1a⁺/⁺) and mdr1a knock-out (mdr1a⁻/⁻) mice received i.p. 10, 20 or 40 mg/kg MDMA. Plasma and brain specimens were collected 0.3-4 h after MDMA, and striatum were dissected. MDMA and metabolites were quantified in plasma and striatum by gas chromatography-mass spectrometry. MDMA maximum plasma concentrations (C(max)) for both strains were 916- 1363, 1833-3546, and 5979-7948 μg/L, whereas brain C(max) were 6673-14,869, 23,428-29,433, and 52,735-66,525 μg/kg after 10, 20, or 40 mg/kg MDMA, respectively. MDMA and metabolite striatum/plasma AUC ratios were similar in both strains, inconsistent with observed MDMA neuroprotective effects in mdr1a⁻/⁻ mice. Ratios of methylenedioxyamphetamine (MDA) and 4-hydroxy-3-methoxymethamphetamine (HMMA) AUCs exceeded 18% of MDMA's in plasma, suggesting substantial MDMA hepatic metabolism in mice. MDMA, MDA, HMMA, and 4-hydroxy-3-methoxyamphetamine maximum concentrations and AUCs exhibited nonlinear relationships during dose-escalation studies, consistent with impaired enzymatic demethylenation. Nonlinear increases in MDMA plasma and brain concentrations with increased MDMA dose may potentiate MDMA effects and toxicity.
authors.affiliation: Chemistry and Drug Metabolism Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Biomedical Research Center, 251 Bayview Boulevard, Baltimore, Maryland 21224, USA.
authors.forename: Karl B
authors.initials: KB
authors.lastname: Scheidweiler
authors.forename: Bruce
authors.initials: B
authors.lastname: Ladenheim
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Barnes
authors.forename: Jean Lud
authors.initials: JL
authors.lastname: Cadet
authors.forename: Marilyn A
authors.initials: MA
authors.lastname: Huestis
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001711:Biotransformation; D003342:Corpus Striatum / Q000378:metabolism*; D003627:Data Interpretation, Statistical; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D020258:Neurotoxicity Syndromes / Q000097:blood / Q000209:etiology / Q000235:genetics; D017711:Nonlinear Dynamics; D051381:Rats; D013045:Species Specificity; D013237:Stereoisomerism; D014018:Tissue Distribution
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; C095122:multidrug resistance protein 3; D018817:N-Methyl-3,4-methylenedioxyamphetamine