title: An integrated pharmacokinetic and pharmacodynamic study of a new drug of abuse, methylone, a synthetic cathinone sold as "bath salts".
abstract: BACKGROUND
  Methylone (3,4-methylenedioxymethcathinone) is a new psychoactive substance and an active ingredient of "legal highs" or "bath salts". We studied the pharmacokinetics and locomotor activity of methylone in rats at doses equivalent to those used in humans.
  
  
  METHODS
  Methylone was administered to male Sprague-Dawley rats intravenously (10mg/kg) and orally (15 and 30 mg/kg). Plasma concentrations and metabolites were characterized by LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180-240 min.
  
  
  RESULTS
  Oral administration of methylone induced a dose-dependent increase in locomotor activity in rats. The plasma concentrations after i.v. administration were described by a two-compartment model with distribution and terminal elimination phases of α=1.95 h(-1) and β=0.72 h(-1). For oral administration, peak methylone concentrations were achieved between 0.5 and 1h and fitted to a flip-flop model. Absolute bioavailability was about 80% and the percentage of methylone protein binding was of 30%. A relationship between methylone brain levels and free plasma concentration yielded a ratio of 1.42 ± 0.06, indicating access to the central nervous system. We have identified four Phase I metabolites after oral administration. The major metabolic routes are N-demethylation, aliphatic hydroxylation and O-methylation of a demethylenate intermediate.
  
  
  CONCLUSIONS
  Pharmacokinetic and pharmacodynamic analysis of methylone showed a correlation between plasma concentrations and enhancement of the locomotor activity. A contribution of metabolites in the activity of methylone after oral administration is suggested. Present results will be helpful to understand the time course of the effects of this drug of abuse in humans.
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry, Pharmacology Section, and Institute of Biomedicine, IBUB, Faculty of Pharmacy, University of Barcelona, Spain.
authors.forename: Raúl
authors.initials: R
authors.lastname: López-Arnau
authors.forename: José
authors.initials: J
authors.lastname: Martínez-Clemente
authors.forename: Marcel li
authors.initials: Ml
authors.lastname: Carbó
authors.forename: David
authors.initials: D
authors.lastname: Pubill
authors.forename: Elena
authors.initials: E
authors.lastname: Escubedo
authors.forename: Jorge
authors.initials: J
authors.lastname: Camarasa
mesh_terms: D000470:Alkaloids / Q000737:chemistry; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D008694:Methamphetamine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats
chemical_list: D000470:Alkaloids; D000697:Central Nervous System Stimulants; D008694:Methamphetamine; C023665:cathinone; C400939:methylone
keywords: 3,4-Methylenedioxycathinone; 3-Hydroxy-3-methoxymethcathinone; 3-OH-4-MeO-MC; 3’-Hydroxy-methylenedioxymethcathinone; 3’-OH-MDMC; 4-Hydroxy-3-methoxymethcathinone; 4-OH-3-MeO-MC; AIC; Akaike’s information criterion; LC/MS; Locomotor activity; MDC; MDMC; Methylone; Methylone (3,4-methylenedioxymethcathinone); PK/PD; PK/PD modeling; Pharmacokinetic/Pharmacodynamics analysis; Pharmacokinetics; Rat; liquid chromatography/mass spectrometry