Nonlinear Pharmacokinetics of (±)3,4-Methylenedioxymethamphetamine (MDMA) and Its Pharmacodynamic Consequences in the Rat

Abstract

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-methylenedioxyamphetamine (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.

Pharmacokinetic Profiles and Pharmacodynamic Effects for Methylone and Its Metabolites in Rats

“…Methylone inhibits human CYP2D6 in vitro (Dinger et al, 2016;Pedersen et al, 2013), and the present non-linear increases in plasma methylone and MDC seem to agree with this observation. It should be mentioned that non-linear kinetics resulting from inhibition of CYP2D1 (ie, the rat isoform of CYP2D6 responsible for methylone O-demethylenation) should result in appreciable decreases in the formation of HHMC and HMMC (see Concheiro et al, 2014). However, Figure 3 illustrates that AUC values for HHMC and HMMC were within the expected range as dose increased, not less than predicted.…”

“…Methylone exhibited rapid kinetics compared with its structural analog MDMA, with T max occurring at 15 min as opposed to 36, 54, and 66 min for 2.5, 5, and 10 mg/kg MDMA, respectively (Concheiro et al, 2014). Owing to the rapid PKs of methylone after sc administration, it is plausible that T max may have occurred even earlier than 15 min, if specimens had been collected earlier.…”

“…It is well established that MDMA displays non-linear PKs in rats and humans (Baumann et al, 2009;Chu et al, 1996;Concheiro et al, 2014;de la Torre et al, 2000;Kolbrich et al, 2008) owing to inhibition of its own metabolism (Heydari et al, 2004;Wu et al, 1997). By contrast, Lopez-Arnau et al (2013) found no evidence for non-linear PKs in rats after oral Figure 5 Dose-response effects of methylone, MDC, HHMC, and HMMC on extracellular dopamine (DA) in male rats undergoing in vivo microdialysis in nucleus accumbens.…”

“…First, methylone is extensively metabolized in a manner similar to its structural analog MDMA, as illustrated by the formation of O-demethylenated metabolites (ie, HHMC and HMMC) and an N-demethylated metabolite (ie, MDC). In general, plasma concentrations of methylone and its metabolites displayed more rapid kinetics when compared with MDMA (Baumann et al, 2009;Concheiro et al, 2014). Second, we Data are EC 50 expressed as nM concentrations (mean ± SD) for N = 3 experiments performed in triplicate.…”

“…The mechanism of action for methylone resembles that of MDMA, which is not surprising considering methylone is the β-keto analog of MDMA. It is notable that MDMA is metabolized by hepatic mechanisms in rats and humans (de la Torre and Farre, 2004), and its bioactive metabolites may contribute to the profile of drug effects in vivo (Concheiro et al, 2014;Schindler et al, 2014). Moreover, MDMA displays non-linear pharmacokinetics (PKs) characterized by increases in plasma drug concentrations that are greater than dose-proportional (Baumann et al, 2009;Chu et al, 1996;de la Torre et al, 2000).…”