Sprague-Dawley rats display sex-linked differences in the pharmacokinetics of 3,4-methylenedioxymethamphetamine (MDMA) and its metabolite 3,4-methylenedioxyamphetamine (MDA)

Journal Article · Tue Dec 15 00:00:00 EST 2009 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2009.09.008· OSTI ID:21344817

Fonsart, Julien ^[1]; Menet, Marie-Claude ^[1]; Debray, Marcel; Hirt, Deborah; Noble, Florence; Scherrmann, Jean-Michel; Decleves, Xavier ^[1]

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1. Universite Paris Descartes, Faculte de Pharmacie, Paris F-75006 (France)

The use of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) has increased in recent years; it can lead to life-threatening hyperthermia and serotonin syndrome. Human and rodent males appear to be more sensitive to acute toxicity than are females. MDMA is metabolized to five main metabolites by the enzymes CYP1A2, CYP2D and COMT. Little is presently known about sex-dependent differences in the pharmacokinetics of MDMA and its metabolites. We therefore analyzed MDMA disposition in male and female rats by measuring the plasma and urine concentrations of MDMA and its metabolites using a validated LC-MS method. MDA AUC{sub last} and C{sub max} were 1.6- to 1.7-fold higher in males than in females given MDMA (5 mg/kg sc), while HMMA C{sub max} and AUC{sub last} were 3.2- and 3.5-fold higher, respectively. MDMA renal clearance was 1.26-fold higher in males, and that of MDA was 2.2-fold higher. MDMA AUC{sub last} and t{sub 1/2} were 50% higher in females given MDMA (1 mg/kg iv). MDA C{sub max} and AUC{sub last} were 75-82% higher in males, with a 2.8-fold higher metabolic index. Finally, the AUC{sub last} of MDA was 0.73-fold lower in males given 1 mg/kg iv MDA. The volumes of distribution of MDMA and MDA at steady-state were similar in the two sexes. These data strongly suggest that differences in the N-demethylation of MDMA to MDA are major influences on the MDMA and MDA pharmacokinetics in male and female rats. Hence, males are exposed to significantly more toxic MDA, which could explain previously reported sexual dysmorphism in the acute effects and toxicity of MDMA in rats.

• OSTI ID: 21344817
• Journal Information: Toxicology and Applied Pharmacology, Vol. 241, Issue 3; Other Information: DOI: 10.1016/j.taap.2009.09.008; PII: S0041-008X(09)00397-4; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

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60 APPLIED LIFE SCIENCES
AMPHETAMINES
BLOOD PLASMA
BLOOD-PLASMA CLEARANCE
CATECHOLAMINES
ENZYMES
KINETICS
MASS SPECTROSCOPY
RATS
RENAL CLEARANCE
TOXICITY
URINE
AMINES
ANALEPTICS
ANIMALS
AROMATICS
AUTONOMIC NERVOUS SYSTEM AGENTS
BIOLOGICAL MATERIALS
BIOLOGICAL WASTES
BLOOD
BODY FLUIDS
CENTRAL NERVOUS SYSTEM AGENTS
CLEARANCE
DRUGS
EXCRETION
HYDROXY COMPOUNDS
MAMMALS
MATERIALS
ORGANIC COMPOUNDS
PHENOLS
POLYPHENOLS
PROTEINS
RODENTS
SPECTROSCOPY
SYMPATHOMIMETICS
VERTEBRATES
WASTES