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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Nonlinear Pharmacokinetics of (±)3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") and Its Major Metabolites in Squirrel Monkeys at Plasma Concentrations of MDMA That Develop After Typical Psychoactive Doses

Department of Neurology (M.M., G.A.R.) and Psychiatry and Behavioral Sciences (U.D.M.), Johns Hopkins University School of Medicine, Baltimore, Maryland; and Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg (Saar), Germany (M.M., F.T.P., H.H.M.)

At certain doses, the psychoactive drug (±)3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") destroys brain serotonin axon terminals. By causing increases in plasma MDMA concentrations that exceed those predicted by the increase in dose, nonlinear pharmacokinetics has the potential to narrow the range between safe and neurotoxic doses of MDMA. The present study sought to determine whether the pharmacokinetics of MDMA in nonhuman primates are nonlinear and, if they are, to identify plasma concentrations of MDMA at which nonlinear accumulation of MDMA occurs. Four different oral doses of MDMA were tested in the same six squirrel monkeys in random order. At each dose, pharmacokinetic parameters for MDMA and its metabolites 3,4-dihydroxymethamphetamine (HHMA), 4-hydroxy-3-methoxymethamphetamine (HMMA), and 3,4-methylenedioxyamphetamine were determined. Doses were selected to be equivalent to 0.4, 0.8, 1.6, and 2.8 mg/kg doses in humans. The maximal concentration (C_max) and area under the curve (AUC) of MDMA increased nonlinearly with dose, whereas the C_max and AUC of the metabolites HHMA and HMMA remained relatively constant. Nonlinear MDMA pharmacokinetics occurred at plasma MDMA concentrations of 100 to 300 ng/ml and above. The half-life (T_1/2) of MDMA and its metabolites also increased with dose. These results firmly establish nonlinear pharmacokinetics for MDMA in squirrel monkeys and indicate that nonlinear MDMA accumulation occurs at plasma MDMA concentrations that develop in humans taking typical doses. By raising MDMA concentrations and prolonging its action, nonlinear pharmacokinetics and T_1/2 prolongation, respectively, may influence the likelihood and severity of MDMA toxicities (including brain serotonin neurotoxicity).

Address correspondence to: Dr. George A. Ricaurte, Department of Neurology, Johns Hopkins Medical Institutions, 5501 Hopkins Bayview Circle, Rm 5B.71E, Baltimore, MD 21224. E-mail: ricaurte{at}jhmi.edu

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				W. E. Fantegrossi, N. Murai, B. O. Mathuna, N. Pizarro, and R. de la Torre Discriminative Stimulus Effects of 3,4-Methylenedioxymethamphetamine and Its Enantiomers in Mice: Pharmacokinetic Considerations J. Pharmacol. Exp. Ther., June 1, 2009; 329(3): 1006 - 1015. [Abstract] [Full Text] [PDF]