Abstract
Based on animal data, there is speculation that (±)-3,4-methylenedioxymethamphetamine (MDMA) is neurotoxic to humans. Extrapolation of MDMA findings from animals to humans requires assessment of pharmacokinetics in various species, and low-dose administration data from rats are lacking. In this study, we examine MDMA pharmacokinetics in rats given low (2 mg/kg) and high (10 mg/kg) doses of racemic MDMA via intraperitoneal, subcutaneous, and oral routes. Repeated blood specimens were collected from venous catheters, and plasma was assayed for MDMA and its metabolites, 4-hydroxy-3-methoxymethamphetamine (HMMA) and 3,4-methylenedioxyamphetamine (MDA), by gas chromatography-mass spectrometry. After 2 mg/kg, maximum MDMA concentrations (Cmax) were ∼200 ng/ml for intraperitoneal and subcutaneous routes, but less for the oral route. MDMA plasma half-lives were <1 h for low-dose groups, whereas HMMA and MDA half-lives were >2 h. After 10 mg/kg, MDMA areas under the curve (AUCs) were 21-fold (intraperitoneal), 10-fold (subcutaneous), and 36-fold (oral) greater than those at 2 mg/kg. In contrast, HMMA AUC values in high-dose groups were <3-fold above those at 2 mg/kg. Several new findings emerge from this report of low-dose MDMA pharmacokinetics in rats. First, 2 mg/kg MDMA in rats can produce MDMA Cmax values similar to those in humans, perhaps explaining why both species discriminate 1.5 mg/kg MDMA in laboratory paradigms. Second, our data provide additional support for nonlinear kinetics of MDMA in rats, and, analogous to humans, this phenomenon appears to involve impaired drug metabolism. Finally, given key similarities between MDMA pharmacokinetics in rats and humans, data from rats may be clinically relevant when appropriate dosing conditions are used.
- MDMA, (±)-3,4-methylenedioxymethamphetamine
- 5-HT, serotonin
- HHMA, (±)-3,4-dihydroxymethamphetamine
- HMMA, (±)-4-hydroxy-3-methoxymethamphetamine
- MDA, (±)-3,4-methylenedioxyamphetamine
- HHA, (±)-3,4-dihydroxyamphetamine
- HMA, (±)-4-hydroxy-3-methoxyamphetamine
- GC, gas chromatography
- MS, mass spectrometry
- HPLC, high-performance liquid chromatography
- ANOVA, analysis of variance
- Cmax, maximum concentration
- AUC, area under the curve
- Tmax, time of maximum concentration
- t1/2, elimination half-life.
Footnotes
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This work was supported by the Intramural Research Program of the National Institutes of Health National Institute of Drug Abuse.
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A portion of the data shown herein was previously presented as follows: Baumann MH, Zolkowska D, Kim I, Scheidweiler KA, Rothman RB, and Huestis MA (2009) Nonlinear kinetics of MDMA in rats. Annual Meeting of the College on Problems of Drug Dependence; 2009 Jun 20–25; Reno, NV. College on Problems of Drug Dependence, Philadelphia, PA.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.109.028506
- Received May 15, 2009.
- Accepted August 12, 2009.
- Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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