PMID- 17574396
OWN - NLM
STAT- MEDLINE
DCOM- 20071018
LR  - 20141120
IS  - 0928-0987 (Print)
IS  - 0928-0987 (Linking)
VI  - 32
IP  - 1
DP  - 2007 Sep
TI  - Inactivation of CYP2D6 by methylenedioxymethamphetamine in different recombinant 
      expression systems.
PG  - 8-16
AB  - Recombinantly expressed CYP450 systems (rCYPs) are often used to screen for 
      irreversible/quasi-irreversible enzyme inhibitors during drug development. The 
      concentration- and time-dependent inactivation of CYP2D6 by 
      methylenedioxymethamphetamine (MDMA) was compared in three different rCYP2D6 
      systems (yeast microsomes, Supersomestrade mark and Bactosomestrade mark) under 
      the conditions of the most commonly used protocols in assessing mechanism-based 
      inactivation (MBI). MDMA (2-20microM) was pre-incubated with enzyme for 0, 2.5 
      and 5min followed by a five-fold dilution and further incubation with 
      dextromethorpan (DEX) (50microM). The formation of dextrorphan (DOR) from DEX was 
      used as a specific marker of CYP2D6 activity. Concentration- and time-dependent 
      inactivation of CYP2D6 by MDMA was observed with each rCYP system. However, the 
      apparent kinetic parameters for MBI (k(inact), the maximum inactivation rate 
      constant and K(I), the inhibitor concentration associated with half maximal rate 
      of inactivation) were significantly greater (p<0.05) for Bactosomestrade mark 
      (0.95+/-0.33min(-1), 42.9+/-20.1microM) than those found using yeast microsomes 
      (0.28+/-0.04min(-1), 2.86+/-1.18microM) and Supersomestrade mark 
      (0.38+/-0.05min(-1), 3.66+/-0.10microM). After correction for depletion of MDMA 
      during pre-incubation, k(inact) and K(I) values determined using Bactosomestrade 
      mark decreased significantly but remained higher than for the other rCYP systems 
      (p<0.05). Substantial metabolism of DOR after its formation from DEX was also 
      observed using Supersomestrade mark and Bactosomestrade mark. Sub-optimal study 
      design when investigating MBI may compromise the quantitative characterization of 
      inhibitory characteristics using some rCYP systems.
FAU - Van, Linh M
AU  - Van LM
AD  - University of Sheffield, Academic Unit of Clinical Pharmacology, University of 
      Sheffield, Sheffield S10 2JF, UK.
FAU - Hargreaves, Judith A
AU  - Hargreaves JA
FAU - Lennard, Martin S
AU  - Lennard MS
FAU - Tucker, Geoffrey T
AU  - Tucker GT
FAU - Rostami-Hodjegan, Amin
AU  - Rostami-Hodjegan A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070522
PL  - Netherlands
TA  - Eur J Pharm Sci
JT  - European journal of pharmaceutical sciences : official journal of the European 
      Federation for Pharmaceutical Sciences
JID - 9317982
RN  - 0 (Cytochrome P-450 CYP2D6 Inhibitors)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Recombinant Proteins)
RN  - 04B7QNO9WS (Dextrorphan)
RN  - 7355X3ROTS (Dextromethorphan)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2D6)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - Cytochrome P-450 CYP2D6/genetics/metabolism
MH  - *Cytochrome P-450 CYP2D6 Inhibitors
MH  - Dextromethorphan/pharmacology
MH  - Dextrorphan/pharmacology
MH  - Enzyme Inhibitors/*pharmacology
MH  - Humans
MH  - Kinetics
MH  - Microsomes/drug effects/enzymology/metabolism
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*pharmacology
MH  - Recombinant Proteins/*antagonists & inhibitors/metabolism
MH  - Saccharomyces cerevisiae/genetics/metabolism
EDAT- 2007/06/19 09:00
MHDA- 2007/10/19 09:00
CRDT- 2007/06/19 09:00
PHST- 2007/02/15 00:00 [received]
PHST- 2007/04/30 00:00 [revised]
PHST- 2007/05/03 00:00 [accepted]
PHST- 2007/06/19 09:00 [pubmed]
PHST- 2007/10/19 09:00 [medline]
PHST- 2007/06/19 09:00 [entrez]
AID - S0928-0987(07)00126-1 [pii]
AID - 10.1016/j.ejps.2007.05.002 [doi]
PST - ppublish
SO  - Eur J Pharm Sci. 2007 Sep;32(1):8-16. doi: 10.1016/j.ejps.2007.05.002. Epub 2007 
      May 22.