Nonlinear Pharmacokinetics of ( 6 )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 MDMA ’ s safety are needed. We evaluated MDMA ’ s pharmacokinetics and metabolism in male rats receiving 2.5, 5, and 10 mg/kg 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 ( 6 )-3,4-dihydroxymethamphetamine (HHMA), ( 6 )-4-hydroxy-3-methoxymethamphetamine (HMMA), and ( 6 )-3,4-methylenediox-yamphetamine (MDA) by liquid chromatography – tandem mass spectrometry. After 2.5 mg/kg MDMA, mean MDMA C max was 164 6 47.1 ng/ml, HHMA and HMMA were major metabolites, and < 20% of MDMA was metabolized to MDA. After 5- and 10-mg/kg doses, MDMA areas under the curve (AUCs) were 3- and 10-fold greater than those after 2.5 mg/kg; 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 MDMA ’ s 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. pharmacodynamic consequences. We report plasma concentrations of MDMA, HHMA, HMMA, and MDA in male rats receiving incremental s.c. MDMA (2.5, 5, and 10 mg/kg). Rats were fitted with indwelling catheters so repeated blood specimens could be collected, while we simultaneously measured 5-HT behavioral syndrome and core body temperature. Our findings reveal that increasing MDMA doses administered to rats produce greater than expected area-under-the curve (AUC) values for MDMA and MDA, while AUCs for HHMA and HMMA were lower than expected. These results provide compelling in vivo evidence that MDMA displays nonlinear accumulation in rats via inhibition of metabolism, similar to the effects in humans. 5-HT syndrome severity correlated with MDMA plasma concentrations, but core temperature correlated with MDA, showing distinct contributions of MDMA and its metabolite MDA to the overall pharmacology of administered MDMA. (cid:1) time), followed by Bonferroni post hoc test. To examine potential relationships between pharmacokinetic and pharmacodynamic endpoints, Pearson ’ s correlation coefficients were calculated using data from individual rats treated with 10 mg/kg MDMA. Specifically, coefficients were generated for MDMA and MDA versus syndrome score and temperature. P , 0.05 was considered the minimal criterion for statistical significance.