( )-3,4-Methylenedioxymethamphetamine and Metabolite Disposition in Plasma and Striatum of Wild-Type and Multidrug Resistance Protein 1a Knock-Out Mice

Scheidweiler, Karl B.; Ladenheim, Bruce; Barnes, Allan J.; Cadet, Jean Lud; Huestis, Marilyn A.

doi:10.1093/anatox/35.7.470

Cited by 10 publications

(9 citation statements)

References 44 publications

(118 reference statements)

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“…Deconjugation was performed because prior metabolism studies demonstrated that methylone metabolites are primarily conjugated [24,25], and commercial conjugated reference standards were unavailable. HHMC and HMMC had significant decreases in concentrations when there was no hydrolysis procedure, similar to MDMA metabolites, 3,4-dihydroxymethamphetamine and 4-hydroxy-3-methoxymethamphetamine [31,32]. These results indicate that HHMC and HMMC are present in rat plasma primarily as conjugated metabolites, which coincides with previous reports [24,25,31,32].…”

Section: Discussionsupporting

confidence: 89%

“…HHMC and HMMC had significant decreases in concentrations when there was no hydrolysis procedure, similar to MDMA metabolites, 3,4-dihydroxymethamphetamine and 4-hydroxy-3-methoxymethamphetamine [31,32]. These results indicate that HHMC and HMMC are present in rat plasma primarily as conjugated metabolites, which coincides with previous reports [24,25,31,32]. Protein precipitation was achieved with perchloric acid after the addition of 4-methylcatechol, which was added to reduce possible adsorption of the dihydroxy-metabolite to precipitated proteins.…”

Section: Discussionmentioning

confidence: 89%

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Quantification of methylone and metabolites in rat and human plasma by liquid chromatography-tandem mass spectrometry

et al. 2015

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Methylone is a commonly abused synthetic cathinone derivative marketed as a ''legal'' alternative to ''ecstasy'' or cocaine. Previous studies examined the metabolism of methylone in vitro and in vivo; 4-hydroxy-3-methoxymethcathinone (HMMC) was identified as the primary metabolite, with other reported minor metabolites, 3,4-methylenedioxycathinone (MDC) and 3,4-dihydroxymethcathinone (HHMC). However, limited information is known about methylone and its metabolites' pharmacokinetics. We developed and fully validated a method for the simultaneous quantification of methylone, HMMC, MDC and HHMC by liquid chromatographytandem mass spectrometry in 100 ll rat and human plasma. b-Glucuronidase was utilized for plasma hydrolysis, followed by perchloric acid protein precipitation and solidphase extraction utilizing cation exchange columns.Chromatographic separation was performed with a Synergi Polar column in gradient mode, and analytes were determined by two multiple reaction monitoring (MRM) transitions. Linear ranges of 0.5-1,000 lg/l (methylone, HMMC and MDC) and 10-1,000 lg/l (HHMC) were achieved. Bias and imprecision were generally acceptable, although quantification of HHMC exhibited variability (16.2-37 %). Extraction efficiencies and ion suppression were 89.9-104 % (for HHMC, 15.9-16.2 %) and \ 11.4 %, respectively. Methylone and metabolites were stable in plasma for 24 h at room temperature, 72 h at 4°C, and after three freeze-thaw cycles (except for a 60 % HMMC increase). Human and rat plasma were cross-validated, documenting that rat plasma quality control samples were accurately quantified against a human plasma calibration curve (-23.8 to 12 % bias). As proof of method, rat plasma specimens were analyzed pre-injection and after subcutaneous administration of methylone at 6 mg/kg from 15 to 480 min post-dosing. Methylone, HMMC, MDC and HHMC concentrations ranged from 1.1 to 1,310, 11.2 to 194, 1.9 to 152 and 24.7 to 188 lg/l, respectively.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 89%

Quantification of methylone and metabolites in rat and human plasma by liquid chromatography-tandem mass spectrometry

et al. 2015

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“…Consistent with studies in humans (Kolbrich et al, 2008;Mueller et al, 2009a;Peiró et al, 2013), other primate species (Mechan et al, 2006;Mueller et al, 2008Mueller et al, , 2009a, as well as rodents (Baumann et al, 2009;Scheidweiler et al, 2011), the pharmacokinetics of MDMA were nonlinear in baboons. Similar to our previous results with oral administration (Mueller et al, 2011), MDMA was absent from baboon plasma after administration of the lower MDMA doses (0.32-1.0 mg/kg; human equivalent of approximately 0.26-1.42 mg/kg; D human 5D animal (W human /W animal ) 0.7 where D 5 dose in milligrams, W 5 weight of the animal in kilograms, and 0.7 is a commonly used and empirically derived exponent).…”

Section: Discussionsupporting

confidence: 79%

Behavioral Effects and Pharmacokinetics of (±)-3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) after Intragastric Administration to Baboons

Goodwin

Mueller

Shell

et al. 2013

J Pharmacol Exp Ther

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(6)-3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") is a popular drug of abuse. We aimed to characterize the behavioral effects of intragastric MDMA in a species closely related to humans and to relate behavioral effects to plasma MDMA and metabolite concentrations. Single doses of MDMA (0.32-7.8 mg/kg) were administered via an intragastric catheter to adult male baboons (N 5 4). Effects of MDMA on food-maintained responding were assessed over a 20-hour period, whereas untrained behaviors and fine-motor coordination were characterized every 30 minutes until 3 hours postadministration. Levels of MDMA and metabolites in plasma were measured in the same animals (n 5 3) after dosing on a separate occasion. MDMA decreased food-maintained responding over the 20-hour period, and systematic behavioral observations revealed increased frequency of bruxism as the dose of MDMA was increased. Drug blood level determinations showed no MDMA after the lower doses of MDMA tested (0.32-1.0 mg/kg) and modest levels after higher MDMA doses (3.2-7.8 mg/kg). High levels of 3,4-dihydroxymethamphetamine (HHMA) were detected after all doses of MDMA, suggesting extensive first-pass metabolism of MDMA in the baboon. The present results demonstrate that MDMA administered via an intragastric catheter produced behavioral effects that have also been reported in humans. Similar to humans, blood levels of MDMA after oral administration may not be predictive of the behavioral effects of MDMA. Metabolites, particularly HHMA, may play a significant role in the behavioral effects of MDMA.

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“…There are discrepancies in whether MDMA follows nonlinear pharmacokinetics in rats, as documented in humans, monkeys, and mice (de la Torre et al, 2000;Kolbrich et al, 2008b;Mueller et al, 2008;Scheidweiler et al, 2011). Green et al (2009Green et al ( , 2012 compared literature values for plasma MDMA concentrations following highdose MDMA administration in rats (i.e., 5-20 mg/kg via i.p., s.c., or po routes) to those produced by low-dose administration in humans (i.e., 0.5-2 mg/kg po).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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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.

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( )-3,4-Methylenedioxymethamphetamine and Metabolite Disposition in Plasma and Striatum of Wild-Type and Multidrug Resistance Protein 1a Knock-Out Mice

Cited by 10 publications

References 44 publications

Quantification of methylone and metabolites in rat and human plasma by liquid chromatography-tandem mass spectrometry

Quantification of methylone and metabolites in rat and human plasma by liquid chromatography-tandem mass spectrometry

Behavioral Effects and Pharmacokinetics of (±)-3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) after Intragastric Administration to Baboons

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

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