Journal Article

(±)-3,4-Methylenedioxymethamphetamine and Metabolite Disposition in Plasma and Striatum of Wild-Type and Multidrug Resistance Protein 1a Knock-Out Mice

Karl B. Scheidweiler, Bruce Ladenheim, Allan J. Barnes, Jean Lud Cadet and Marilyn A. Huestis

in Journal of Analytical Toxicology

Volume 35, issue 7, pages 470-480
Published in print September 2011 | ISSN: 0146-4760
Published online September 2011 | e-ISSN: 1945-2403 | DOI: http://dx.doi.org/10.1093/anatox/35.7.470
(±)-3,4-Methylenedioxymethamphetamine and Metabolite Disposition in Plasma and Striatum of Wild-Type and Multidrug Resistance Protein 1a Knock-Out Mice

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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 (Cmax) for both strains were 916–1363, 1833–3546, and 5979–7948 µg/L, whereas brain Cmax 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.

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Subjects: Medical Toxicology ; Toxicology (Non-medical)

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