PMID- 19299523
OWN - NLM
STAT- MEDLINE
DCOM- 20090925
LR  - 20181211
IS  - 1521-009X (Electronic)
IS  - 0090-9556 (Linking)
VI  - 37
IP  - 6
DP  - 2009 Jun
TI  - The role of human hepatic cytochrome P450 isozymes in the metabolism of racemic 
      3,4-methylenedioxyethylamphetamine and its single enantiomers.
PG  - 1152-6
LID - 10.1124/dmd.108.026203 [doi]
AB  - The 3,4-methylenedioxy-methamphetamine (MDMA)-related designer drug 
      3,4-methylenedioxyethylamphetamine (MDEA, Eve) is a chiral compound that is 
      mainly metabolized by N-deethylation and demethylenation during phase I 
      metabolism. The involvement of several cytochrome P450 (P450) isozymes in these 
      metabolic steps has been demonstrated by inhibition assays using human liver 
      microsomes. However, a comprehensive study on the involvement of all relevant 
      human P450s has not been published yet. In addition, the chirality of this drug 
      was not considered in these in vitro studies. The aim of the present work was 
      first to elucidate the contribution of the relevant human P450 isozymes in the 
      demethylenation as well as in the N-dealkylation of racemic MDEA and its single 
      enantiomers and secondly to compare these findings with recently published data 
      concerning the enantioselective metabolism of MDMA. Racemic MDEA and its single 
      enantiomers were incubated using heterologously expressed human P450s, and the 
      corresponding metabolites dihydroxyethylamphetamine and methylenedioxyamphetamine 
      were determined by gas chromatography-mass spectrometry after chiral 
      derivatization with S-heptafluorobutyrylprolyl chloride. The highest 
      contributions to both metabolic steps as calculated from the enzyme kinetic data 
      were obtained for CYP3A4 and CYP2D6 at substrate concentrations corresponding to 
      plasma concentrations of recreational users after intake of racemic MDEA. Both 
      metabolic reactions were found to be enantioselective with a general preference 
      for the S-enantiomers, which was particularly pronounced in the case of CYP2C19. 
      In conclusion, different pharmacokinetic properties of MDEA enantiomers observed 
      in vivo are therefore partially caused by P450-dependent enantioselective 
      metabolism.
FAU - Meyer, Markus R
AU  - Meyer MR
AD  - Department of Experimental and Clinical Toxicology, Institute of Experimental and 
      Clinical Pharmacology and Toxicology, Saarland University, Homburg (Saar), 
      Germany.
FAU - Peters, Frank T
AU  - Peters FT
FAU - Maurer, Hans H
AU  - Maurer HH
LA  - eng
PT  - Journal Article
DEP - 20090319
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (Cytochrome P-450 Enzyme Inhibitors)
RN  - 0 (Designer Drugs)
RN  - 0 (Isoenzymes)
RN  - 4764-17-4 (3,4-Methylenedioxyamphetamine)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - CK833KGX7E (Amphetamine)
RN  - EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases)
RN  - EC 1.14.14.1 (CYP2C19 protein, human)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2C19)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2D6)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP3A)
RN  - EC 1.14.14.55 (CYP3A4 protein, human)
RN  - ML1I4KK67B (3,4-methylenedioxyethamphetamine)
SB  - IM
MH  - 3,4-Methylenedioxyamphetamine/*analogs & derivatives/*metabolism
MH  - Amphetamine/pharmacology
MH  - Aryl Hydrocarbon Hydroxylases/*metabolism
MH  - Cytochrome P-450 CYP2C19
MH  - Cytochrome P-450 CYP2D6/metabolism
MH  - Cytochrome P-450 CYP3A
MH  - Cytochrome P-450 Enzyme Inhibitors
MH  - Cytochrome P-450 Enzyme System/metabolism
MH  - Designer Drugs
MH  - Gas Chromatography-Mass Spectrometry
MH  - Humans
MH  - Isoenzymes/metabolism
MH  - Microsomes, Liver/*enzymology
MH  - Stereoisomerism
MH  - Substrate Specificity
EDAT- 2009/03/21 09:00
MHDA- 2009/09/26 06:00
CRDT- 2009/03/21 09:00
PHST- 2009/03/21 09:00 [entrez]
PHST- 2009/03/21 09:00 [pubmed]
PHST- 2009/09/26 06:00 [medline]
AID - dmd.108.026203 [pii]
AID - 10.1124/dmd.108.026203 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2009 Jun;37(6):1152-6. doi: 10.1124/dmd.108.026203. Epub 2009 
      Mar 19.