title: Pharmacokinetic Profiles and Pharmacodynamic Effects for Methylone and Its Metabolites in Rats.
abstract: 3,4-Methylenedioxy-N-methylcathinone (methylone) is a new psychoactive substance and the β-keto analog of 3,4-methylenedioxy-N-methylamphetamine (MDMA). It is well established that MDMA metabolism produces bioactive metabolites. Here we tested the hypothesis that methylone metabolism in rats can form bioactive metabolites. First, we examined the pharmacokinetics (PKs) of methylone and its metabolites after subcutaneous (sc) methylone administration (3, 6, 12 mg/kg) to male rats fitted with intravenous (iv) catheters for repeated blood sampling. Plasma specimens were assayed by liquid chromatography tandem mass spectrometry to quantify methylone and its phase I metabolites: 3,4-methylenedioxycathinone (MDC), 3,4-dihydroxy-N-methylcathinone (HHMC), and 4-hydroxy-3-methoxy-N-methylcathinone (HMMC). The biological activity of methylone and its metabolites was then compared using in vitro transporter assays and in vivo microdialysis in rat nucleus accumbens. For the PK study, we found that methylone and MDC peaked early (Tmax=15-45 min) and were short lived (t1/2=60-90 min), while HHMC and HMMC peaked later (Tmax=60-120 min) and persisted (t1/2=120-180 min). Area-under-the-curve values for methylone and MDC were greater than dose-proportional, suggesting non-linear accumulation. Methylone produced significant locomotor activation, which was correlated with plasma methylone, MDC, and HHMC concentrations. Methylone, MDC, and HHMC were substrate-type releasers at monoamine transporters as determined in vitro, but only methylone and MDC (1, 3 mg/kg, iv) produced significant elevations in brain extracellular dopamine and 5-HT in vivo. Our findings demonstrate that methylone is extensively metabolized in rats, but MDC is the only centrally active metabolite that could contribute to overall effects of the drug in vivo.
authors.affiliation: Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Elmore
authors.affiliation: Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Ora
authors.initials: O
authors.lastname: Dillon-Carter
authors.affiliation: Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Partilla
authors.affiliation: Chemistry & Drug Metabolism Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.|Program in Toxicology, University of Maryland at Baltimore, Baltimore, MD, USA.
authors.forename: Kayla N
authors.initials: KN
authors.lastname: Ellefsen
authors.affiliation: Chemistry & Drug Metabolism Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.|Department of Sciences, John Jay College of Criminal Justice, City University of New York, New York, NY, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Concheiro
authors.affiliation: Drug Design and Synthesis Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA.
authors.forename: Masaki
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Drug Design and Synthesis Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA.
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.affiliation: Chemistry & Drug Metabolism Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Marilyn A
authors.initials: MA
authors.lastname: Huestis
authors.affiliation: Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Baumann
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D017551:Microdialysis; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000697:Central Nervous System Stimulants; D008694:Methamphetamine; C400939:methylone