PMID- 19781562
OWN - NLM
STAT- MEDLINE
DCOM- 20091202
LR  - 20131121
IS  - 1096-0333 (Electronic)
IS  - 0041-008X (Linking)
VI  - 241
IP  - 3
DP  - 2009 Dec 15
TI  - Sprague-Dawley rats display sex-linked differences in the pharmacokinetics of 
      3,4-methylenedioxymethamphetamine (MDMA) and its metabolite 
      3,4-methylenedioxyamphetamine (MDA).
PG  - 339-47
LID - 10.1016/j.taap.2009.09.008 [doi]
AB  - The use of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) has increased in 
      recent years; it can lead to life-threatening hyperthermia and serotonin 
      syndrome. Human and rodent males appear to be more sensitive to acute toxicity 
      than are females. MDMA is metabolized to five main metabolites by the enzymes 
      CYP1A2, CYP2D and COMT. Little is presently known about sex-dependent differences 
      in the pharmacokinetics of MDMA and its metabolites. We therefore analyzed MDMA 
      disposition in male and female rats by measuring the plasma and urine 
      concentrations of MDMA and its metabolites using a validated LC-MS method. MDA 
      AUC(last) and C(max) were 1.6- to 1.7-fold higher in males than in females given 
      MDMA (5 mg/kg sc), while HMMA C(max) and AUC(last) were 3.2- and 3.5-fold higher, 
      respectively. MDMA renal clearance was 1.26-fold higher in males, and that of MDA 
      was 2.2-fold higher. MDMA AUC(last) and t(1/2) were 50% higher in females given 
      MDMA (1 mg/kg iv). MDA C(max) and AUC(last) were 75-82% higher in males, with a 
      2.8-fold higher metabolic index. Finally, the AUC(last) of MDA was 0.73-fold 
      lower in males given 1 mg/kg iv MDA. The volumes of distribution of MDMA and MDA 
      at steady-state were similar in the two sexes. These data strongly suggest that 
      differences in the N-demethylation of MDMA to MDA are major influences on the 
      MDMA and MDA pharmacokinetics in male and female rats. Hence, males are exposed 
      to significantly more toxic MDA, which could explain previously reported sexual 
      dysmorphism in the acute effects and toxicity of MDMA in rats.
FAU - Fonsart, Julien
AU  - Fonsart J
AD  - Universite Paris Descartes, Faculte de Pharmacie, Paris F-75006, France. 
      julien.fonsart@lrb.aphp.fr
FAU - Menet, Marie-Claude
AU  - Menet MC
FAU - Debray, Marcel
AU  - Debray M
FAU - Hirt, Deborah
AU  - Hirt D
FAU - Noble, Florence
AU  - Noble F
FAU - Scherrmann, Jean-Michel
AU  - Scherrmann JM
FAU - Decleves, Xavier
AU  - Decleves X
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090923
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Hallucinogens)
RN  - 4764-17-4 (3,4-Methylenedioxyamphetamine)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - 3,4-Methylenedioxyamphetamine/pharmacokinetics
MH  - Animals
MH  - Area Under Curve
MH  - Biotransformation
MH  - Calibration
MH  - Chromatography, Liquid
MH  - Female
MH  - Hallucinogens/*pharmacokinetics
MH  - Injections, Intravenous
MH  - Male
MH  - Mass Spectrometry
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*pharmacokinetics
MH  - Quality Control
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Sex Characteristics
EDAT- 2009/09/29 06:00
MHDA- 2009/12/16 06:00
CRDT- 2009/09/29 06:00
PHST- 2009/07/15 00:00 [received]
PHST- 2009/09/06 00:00 [revised]
PHST- 2009/09/14 00:00 [accepted]
PHST- 2009/09/29 06:00 [entrez]
PHST- 2009/09/29 06:00 [pubmed]
PHST- 2009/12/16 06:00 [medline]
AID - S0041-008X(09)00397-4 [pii]
AID - 10.1016/j.taap.2009.09.008 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2009 Dec 15;241(3):339-47. doi: 
      10.1016/j.taap.2009.09.008. Epub 2009 Sep 23.