( )-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.