PMID- 18725511
OWN - NLM
STAT- MEDLINE
DCOM- 20091113
LR  - 20131121
IS  - 1521-009X (Electronic)
IS  - 0090-9556 (Linking)
VI  - 36
IP  - 11
DP  - 2008 Nov
TI  - The role of human hepatic cytochrome P450 isozymes in the metabolism of racemic 
      3,4-methylenedioxy-methamphetamine and its enantiomers.
PG  - 2345-54
LID - 10.1124/dmd.108.021543 [doi]
AB  - The entactogen, 3,4-methylenedioxy-methamphetamine (MDMA), is a chiral drug that 
      is mainly metabolized by N-demethylation and demethylenation. The involvement of 
      cytochrome P450 (P450) isozymes in these metabolic steps has been studied by 
      inhibition assays with human liver microsomes and, in part, with heterologously 
      expressed human P450 isozymes. 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 to study the contribution of human P450 isozymes in the 
      N-demethylation and demethylenation of racemic MDMA and its single enantiomers. 
      MDMA and its enantiomers were incubated using heterologously expressed human 
      P450s, and the metabolites were quantified by gas chromatography-mass 
      spectrometry after derivatization with S-heptafluorobutyrylprolyl chloride. The 
      highest contribution for the N-demethylation as calculated from the enzyme 
      kinetic data, were obtained for CYP2B6 (R,S-MDMA), CYP1A2 (R-MDMA), and CYP2B6 
      (S-MDMA). In the case of the demethylenation, the isozyme with the highest 
      contribution to net clearance for R,S-MDMA, R-MDMA, and S-MDMA was CYP2D6. For 
      the first time, marked enantioselectivity was observed for N-demethylation and 
      demethylenation by CYP2C19 with a preference for the S-enantiomers. In addition, 
      CYP2D6 showed preference for S-MDMA in the case of demethylenation. None of the 
      other isozymes showed major preferences for certain enantiomers. In conclusion, 
      therefore, the different pharmacokinetic properties of the MDMA enantiomers may 
      be caused by enantioselective metabolism by CYP2C19 and CYP2D6.
FAU - Meyer, Markus R
AU  - Meyer MR
AD  - Department of Experimental and Clinical Toxicology, Institute of Experimental and 
      Clinical Pharmacology and Toxicology, Saarland University, Building 46, D-66421 
      Homburg (Saar), Germany.
FAU - Peters, Frank T
AU  - Peters FT
FAU - Maurer, Hans H
AU  - Maurer HH
LA  - eng
PT  - Comparative Study
PT  - Journal Article
DEP - 20080825
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (Isoenzymes)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP1A2)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2D6)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - Cytochrome P-450 CYP1A2/chemistry/*physiology
MH  - Cytochrome P-450 CYP2D6/chemistry/*physiology
MH  - Humans
MH  - Isoenzymes/chemistry/physiology
MH  - Liver/enzymology/metabolism
MH  - Microsomes, Liver/enzymology/*metabolism
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*chemistry/*pharmacokinetics
MH  - Stereoisomerism
EDAT- 2008/08/30 09:00
MHDA- 2009/11/17 06:00
CRDT- 2008/08/30 09:00
PHST- 2008/08/30 09:00 [pubmed]
PHST- 2009/11/17 06:00 [medline]
PHST- 2008/08/30 09:00 [entrez]
AID - dmd.108.021543 [pii]
AID - 10.1124/dmd.108.021543 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2008 Nov;36(11):2345-54. doi: 10.1124/dmd.108.021543. Epub 
      2008 Aug 25.