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The present study was undertaken to examine the drug interactions between 3,4-methylenedioxymethamphetamine (MDMA) and paroxetine or several compounds including the 3,4-methylenedioxybenzyl (piperonyl) group in mice. The time course of radioactivity in the mouse brain after i.v. administration of the tracer amount (approximately 70 ng/kg) of [3H]MDMA was altered significantly by coinjection of carrier MDMA (15 mg/kg) or by pretreatment with paroxetine (10 mg/kg, i.p., 5 min). Furthermore, the radioactivity in the brain 60 min after injection of [3H]MDMA was increased significantly by pretreatment with paroxetine, but not by pretreatment with 6-nitroquipazine, fluoxetine, clomipramine, GBR 12909 or desipramine, indicating that paroxetine-induced alteration of the brain radioactivity was not due to the inhibitory effect of 5-hydroxytryptamine (5-HT) uptake of paroxetine. The radioactivity in the brain 60 min after injection of [3H]MDMA was increased significantly by pretreatment with 3,4-methylenedioxyamphetamine (MDA), MDMA, 1-piperonylpiperazine and N, alpha-dimethylpiperonylamine, but not by pretreatment with piperonylacetone, piperonyl butoxide and piperonyl isobutyrate. HPLC analyses indicated that the alteration of brain radioactivity 60 min after injection of [3H]MDMA was, in part, due to inhibition in the metabolism of [3H]MDMA to radioactive metabolite(s). The present results suggest that a specific mechanism for the 3,4-methylenedioxyphenyl group which rapidly alters the disposition and metabolism of [3H]MDMA may exist in brain and peripheral organs of mice.

A gas chromatography-mass spectrometry assay based on perfluorotributylamine-enhanced ammonia positive ion chemical ionization has been developed for MDMA and three of its primary metabolites in biological specimens; the assay is linear from 2 to 1000 ng ml-1. Quantitatively, more of an administered dose of 10 mg kg-1 MDMA was excreted by the mouse (72%) than by the rat (35%); most in both species was excreted in urine and within 24 h. The difference in per cent excretion is entirely due to proportionally greater excretion of the parent drug by the mouse. 4-Hydroxy-3-methoxymethamphetamine (HMM) is the major urinary metabolite in both species. HMM and another primary metabolite, 4-hydroxy-3-methoxyamphetamine (HMA), were excreted mainly as glucuronide and sulphate conjugates (> 85%).

Interpretation of the in vivo actions of 3,4-methylenedioxymethamphetamine (MDMA) is complicated by the formation of the active metabolite, 3,4-methylenedioxyamphetamine (MDA). This study evaluates the role of MDA in the dopamine releasing actions of (+)-MDMA. In the study, rats were given subcutaneous doses of (+)-MDMA and concentrations of monoamines and their metabolites in striatal dialysate were measured at 15 min intervals. In parallel experiments, plasma concentrations of (+)- and (-)-MDMA and MDA were determined by GC/MS procedures. The time course of MDMA levels was comparable for the two isomers as were their bioavailabilities. In contrast, the plasma levels of MDA were about three times higher after (+)-MDMA. (+)-MDMA caused a rapid increase in striatal dialysate levels of dopamine and decreased extracellular levels of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). There was a significant correlation between dopamine concentration in striatal dialysate and plasma MDMA concentration, but not with plasma MDA. These results indicate that MDMA itself has stereoselective actions on dopamine neurons. However, the higher plasma MDA levels after (+)-MDMA may account for part of the enantiomeric differences in the behavioral and neurotoxicological effects of MDMA.