PMID- 24141857
OWN - NLM
STAT- MEDLINE
DCOM- 20140815
LR  - 20211021
IS  - 1521-009X (Electronic)
IS  - 0090-9556 (Print)
IS  - 0090-9556 (Linking)
VI  - 42
IP  - 1
DP  - 2014 Jan
TI  - Nonlinear pharmacokinetics of (+/-)3,4-methylenedioxymethamphetamine (MDMA) and 
      its pharmacodynamic consequences in the rat.
PG  - 119-25
LID - 10.1124/dmd.113.053678 [doi]
AB  - 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 
      (+/-)-3,4-dihydroxymethamphetamine (HHMA), (+/-)-4-hydroxy-3-methoxymethamphetamine 
      (HMMA), and (+/-)-3,4-methylenedioxyamphetamine (MDA) by liquid 
      chromatography-tandem mass spectrometry. After 2.5 mg/kg MDMA, mean MDMA Cmax was 
      164 +/- 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.
FAU - Concheiro, Marta
AU  - Concheiro M
AD  - Chemistry and Drug Metabolism Section (M.C., K.B.S., M.A.H.), and Designer Drug 
      Research Unit (M.H.B., R.B.R.), Intramural Research Program, National Institute 
      on Drug Abuse, National Institutes of Health, Baltimore, Maryland; and Department 
      of Neuroscience, Weill Cornell Medical College, New York, New York (G.F.M.).
FAU - Baumann, Michael H
AU  - Baumann MH
FAU - Scheidweiler, Karl B
AU  - Scheidweiler KB
FAU - Rothman, Richard B
AU  - Rothman RB
FAU - Marrone, Gina F
AU  - Marrone GF
FAU - Huestis, Marilyn A
AU  - Huestis MA
LA  - eng
GR  - Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20131018
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 117652-28-5 (4-hydroxy-3-methoxymethamphetamine)
RN  - 333DO1RDJY (Serotonin)
RN  - 44RAL3456C (Methamphetamine)
RN  - 4764-17-4 (3,4-Methylenedioxyamphetamine)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - 3,4-Methylenedioxyamphetamine/pharmacokinetics/pharmacology
MH  - Animals
MH  - Area Under Curve
MH  - Male
MH  - Methamphetamine/analogs & derivatives/pharmacokinetics/pharmacology
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*pharmacokinetics/*pharmacology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Serotonin/metabolism
PMC - PMC3876787
EDAT- 2013/10/22 06:00
MHDA- 2014/08/16 06:00
PMCR- 2014/01/01
CRDT- 2013/10/22 06:00
PHST- 2013/10/22 06:00 [entrez]
PHST- 2013/10/22 06:00 [pubmed]
PHST- 2014/08/16 06:00 [medline]
PHST- 2014/01/01 00:00 [pmc-release]
AID - dmd.113.053678 [pii]
AID - DMD_053678 [pii]
AID - 10.1124/dmd.113.053678 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2014 Jan;42(1):119-25. doi: 10.1124/dmd.113.053678. Epub 2013 
      Oct 18.