Stereochemical differences in the metabolism of 3,4-methylenedioxymethamphetamine in vivo and in vitro: a pharmacokinetic analysis.

The in vivo N-demethylation of (+) and (-)3,4-methylenedioxymethamphetamine (MDMA) to 3,4-methylenedioxyamphetamine (MDA) was determined and the pharmacokinetic relationship between the two compounds calculated. The levels of MDA formed after iv administration of (+)MDMA to male rats were about 3 times greater than those for (-)MDMA, although the plasma levels of the parent drugs were comparable. Plasma MDA concentrations were lower in phenobarbital-pretreated rats, but SKF 525-A pretreatment, at the dose used, had minimal effects. In liver microsome experiments conducted with microM concentrations of (+)MDMA, 3,4-dihydroxymethamphetamine (N-methyl-alpha-methyldopamine) was shown to be the major metabolite. MDA was also formed in vitro, but the enantioselectivity was the opposite of that found in vivo, pointing out the difficulties in extrapolation of in vitro observations to in vivo disposition. The high levels of MDA observed after administration of (+)MDMA to intact animals suggest that this active metabolite could be important in the overall effects of (+)MDMA.