Hydrolysis of 3,4-methylenedioxymethamphetamine (MDMA) metabolite conjugates in human, squirrel monkey, and rat plasma

Mueller, Melanie; Kolbrich-Spargo, Erin A.; Peters, Frank T.; Huestis, Marilyn A.; Ricaurte, George A.; Maurer, Hans H.

doi:10.1007/s00216-009-2607-1

Cited by 15 publications

(18 citation statements)

References 35 publications

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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: 90%

“…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: 92%

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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: 90%

Section: Discussionmentioning

confidence: 92%

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

et al. 2015

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“…Both enzymatic and acid hydrolysis were investigated. Mueller et al [28] have found that acid hydrolysis maximises cleavage of both glucuronic and sulfuric acid conjugates for MDMA metabolites in human samples. However in our hands, acid hydrolysis was found to cause a marked decrease in recovery of AM and MA and the presence of acid also interfered with the derivatization of analytes.…”

Section: Resultsmentioning

confidence: 98%

Stereoselective method development and validation for determination of concentrations of amphetamine-type stimulants and metabolites in human urine using a simultaneous extraction–chiral derivatization approach

Raihana

Gan

Tan

2011

Journal of Chromatography B

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“…Total amounts (conjugated and free) of HHMA and HMMA were determined. The procedure employed for cleavage of conjugates in rat plasma has been optimized and found to be reproducible (Mueller et al, 2009b). The linear range for the method used in the present study was 20-1000 ng/ml for HHMA, HMMA, and MDMA and 10-500 ng/ml for MDA.…”

Section: Methodsmentioning

confidence: 87%

Studies of (±)-3,4-Methylenedioxymethamphetamine (MDMA) Metabolism and Disposition in Rats and Mice: Relationship to Neuroprotection and Neurotoxicity Profile

Mueller

Maldonado-Adrian

Yuan

et al. 2012

J Pharmacol Exp Ther

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The neurotoxicity of (6)-3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy") is influenced by temperature and varies according to species. The mechanisms underlying these two features of MDMA neurotoxicity are unknown, but differences in MDMA metabolism have recently been implicated in both. The present study was designed to 1) assess the effect of hypothermia on MDMA metabolism, 2) determine whether the neuroprotective effect of hypothermia is related to inhibition of MDMA metabolism, and 3) determine if different neurotoxicity profiles in mice and rats are related to differences in MDMA metabolism and/or disposition in the two species. Rats and mice received single neurotoxic oral doses of MDMA at 25°C and 4°C, and body temperature, pharmacokinetic parameters, and serotonergic and dopaminergic neuronal markers were measured.Hypothermia did not alter MDMA metabolism in rats and only modestly inhibited MDMA metabolism in mice; however, it afforded complete neuroprotection in both species. Rats and mice metabolized MDMA in a similar pattern, with 3,4-methylenedioxyamphetamine being the major metabolite, followed by 4-hydroxy-3-methoxymethamphetamine and 3,4-dihydroxymethamphetamine, respectively. Differences between MDMA pharmacokinetics in rats and mice, including faster elimination in mice, did not account for the different profile of MDMA neurotoxicity in the two species. Taken together, the results of these studies indicate that inhibition of MDMA metabolism is not responsible for the neuroprotective effect of hypothermia in rodents, and that different neurotoxicity profiles in rats and mice are not readily explained by differences in MDMA metabolism or disposition.

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Hydrolysis of 3,4-methylenedioxymethamphetamine (MDMA) metabolite conjugates in human, squirrel monkey, and rat plasma

Cited by 15 publications

References 35 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

Stereoselective method development and validation for determination of concentrations of amphetamine-type stimulants and metabolites in human urine using a simultaneous extraction–chiral derivatization approach

Studies of (±)-3,4-Methylenedioxymethamphetamine (MDMA) Metabolism and Disposition in Rats and Mice: Relationship to Neuroprotection and Neurotoxicity Profile

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