Nonlinear pharmacokinetics of (-)3,4-methylenedioxymethamphetamine (MDMA) and its pharmacodynamic consequences in the rat.
3,4-Methylenedioxymethamphetamine (MDMA) is a widely abused illicit drug that can cause severe and even fatal adverse effects. However, interest remains for its possible clinical applications in posttraumatic stress disorder and anxiety treatment. Preclinical studies to determine MDMAs safety are needed. We evaluated MDMAs pharmacokinetics and metabolism in male rats receiving 2.5, 5, and 10 mgkg s.c. MDMA, and the associated pharmacodynamic consequences. Blood was collected via jugular catheter at 0, 0.5, 1, 2, 4, 6, 8, 16, and 24 hours, with simultaneous serotonin (5-HT) behavioral syndrome and core temperature monitoring. Plasma specimens were analyzed for MDMA and the metabolites (±)-3,4-dihydroxymethamphetamine (HHMA), (±)-4-hydroxy-3-methoxymethamphetamine (HMMA), and (±)-3,4-methylenedioxyamphetamine (MDA) by liquid chromatography-tandem mass spectrometry. After 2.5 mgkg MDMA, mean MDMA Cmax was 164 ± 47.1 ngml, HHMA and HMMA were major metabolites, and <20% of MDMA was metabolized to MDA. After 5- and 10-mgkg doses, MDMA areas under the curve (AUCs) were 3- and 10-fold greater than those after 2.5 mgkg HHMA and HMMA AUC values were relatively constant across doses and MDA AUC values were greater than dose-proportional. Our data provide decisive in vivo evidence that MDMA and MDA display nonlinear accumulation via metabolic autoinhibition in the rat. Importantly, 5-HT syndrome severity correlated with MDMA concentrations (r 0.8083 P < 0.0001) and core temperature correlated with MDA concentrations (r 0.7595 P < 0.0001), suggesting that MDMAs behavioral and hyperthermic effects may involve distinct mechanisms. Given key similarities between MDMA pharmacokinetics in rats and humans, data from rats can be useful when provided at clinically relevant doses.