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Effects of Dose and Route of Administration on Pharmacokinetics of ({+/-})-3,4-Methylenedioxymethamp

Effects of Dose and Route of Administration on Pharmacokinetics of ({+/-})-3,4-Methylenedioxymethamp

  1. Jatelka
    Drug Metabolism and Disposition 2009 Aug 13. [Epub ahead of print]

    Baumann MH, Zolkowska D, Kim I, Scheidweiler KB, Rothman RB, Huestis MA.

    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. Here we examine MDMA pharmacokinetics in rats given low (2 mg/kg) and high (10 mg/kg) doses of racemic MDMA via i.p., s.c. and p.o. 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 i.p. and s.c. routes, but less for the p.o. route. MDMA plasma half-lives were < 1 h for low-dose groups, while HMMA and MDA half-lives were > 2 h. After 10 mg/kg, MDMA areas-under-the-curve (AUC) were 21-fold (i.p.), 10-fold (s.c.) and 36-fold (p.o.) greater than those at 2 mg/kg. By 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 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 non-linear 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 employed.