title: Chiral Plasma Pharmacokinetics of 3,4-Methylenedioxymethamphetamine and its Phase I and II Metabolites following Controlled Administration to Humans.
abstract: Generally, pharmacokinetic studies on 3,4-methylenedioxymethamphetamine (MDMA) in blood have been performed after conjugate cleavage, without taking into account that phase II metabolites represent distinct chemical entities with their own effects and stereoselective pharmacokinetics. The aim of the present study was to stereoselectively investigate the pharmacokinetics of intact glucuronide and sulfate metabolites of MDMA in blood plasma after a controlled single MDMA dose. Plasma samples from 16 healthy participants receiving 125 mg of MDMA orally in a controlled study were analyzed using liquid chromatography-tandem mass spectroscopy after chiral derivatization. Pharmacokinetic parameters of R- and S-stereoisomers were determined. Sulfates of 3,4-dihydroxymethamphetamine (DHMA), and sulfate and glucuronide of 4-hydroxy-3-methoxymethamphetamine (HMMA) were identified, whereas free phase I metabolites were not detected. Stereoselective differences in Cmax and AUC24 were observed with the following preferences: R>S for MDMA and DHMA 4-sulfate; S>R for 3,4-methylenedioxyamphetamine (MDA), DHMA 3-sulfate, and HMMA glucuronide; and no preference in Cmax for HMMA sulfate. R/S ratios were >1 for all analytes after 24 hours, independent of the initial chiral preference. These are the first data on chiral pharmacokinetics of MDMA phase II metabolites in human plasma in vivo after controlled administration. The main human MDMA metabolites were shown to be sulfate and glucuronide conjugates.
authors.affiliation: Department of Forensic Pharmacology and Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Switzerland (A.E.S, C.S., T.K.); Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, Switzerland (Y.S., A.R., M.E.L.) andrea.steuer@irm.uzh.ch.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Steuer
authors.affiliation: Department of Forensic Pharmacology and Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Switzerland (A.E.S, C.S., T.K.); Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, Switzerland (Y.S., A.R., M.E.L.).
authors.forename: Corina
authors.initials: C
authors.lastname: Schmidhauser
authors.affiliation: Department of Forensic Pharmacology and Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Switzerland (A.E.S, C.S., T.K.); Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, Switzerland (Y.S., A.R., M.E.L.).
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Schmid
authors.affiliation: Department of Forensic Pharmacology and Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Switzerland (A.E.S, C.S., T.K.); Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, Switzerland (Y.S., A.R., M.E.L.).
authors.forename: Anna
authors.initials: A
authors.lastname: Rickli
authors.affiliation: Department of Forensic Pharmacology and Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Switzerland (A.E.S, C.S., T.K.); Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, Switzerland (Y.S., A.R., M.E.L.).
authors.forename: Matthias E
authors.initials: ME
authors.lastname: Liechti
authors.affiliation: Department of Forensic Pharmacology and Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Switzerland (A.E.S, C.S., T.K.); Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, Switzerland (Y.S., A.R., M.E.L.).
authors.forename: Thomas
authors.initials: T
authors.lastname: Kraemer
mesh_terms: D015104:3,4-Methylenedioxyamphetamine / Q000008:administration & dosage* / Q000097:blood* / Q000737:chemistry; D000284:Administration, Oral; D000328:Adult; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry; D013237:Stereoisomerism; D055815:Young Adult
chemical_list: C079646:4-hydroxy-3-methoxymethamphetamine; D008694:Methamphetamine; D015104:3,4-Methylenedioxyamphetamine