PMID- 17387004
OWN - NLM
STAT- MEDLINE
DCOM- 20070716
LR  - 20141120
IS  - 0928-0987 (Print)
IS  - 0928-0987 (Linking)
VI  - 31
IP  - 1
DP  - 2007 May
TI  - Kinetics of the time-dependent inactivation of CYP2D6 in cryopreserved human 
      hepatocytes by methylenedioxymethamphetamine (MDMA).
PG  - 53-61
AB  - Methylenedioxymethamphetamine (MDMA) was investigated in cryopreserved human 
      hepatocytes as a time-dependent inactivator (TDI) of CYP2D6 using 
      dextromethorphan (DEX) as a probe substrate. Inhibition kinetic parameters 
      k(inact), the maximal rate of inactivation, and K(I), the inhibitor concentration 
      at half the maximal activation rate, were determined. Time- and 
      concentration-dependent inhibition were confirmed, and the influence of different 
      elements of study design (e.g. cell number, stability of hepatocytes, dilution 
      after preincubation) on estimated kinetic parameters were evaluated. Dilution 
      factors (DF) of 1.2, 5 or total removal of inhibitor (by washing cells after 
      preincubation, WR) resulted in k(inact) and K(I) (+/-S.E.) values of 0.02+/-0.002 
      min(-1) and 0.88+/-0.31 microM, 0.01+/-0.001 min(-1) and 1.23+/-0.70 microM, and 
      0.01+/-0.001 min(-1) and 2.10+/-1.32 microM, respectively; indicating that 
      insufficient dilution may lead to overestimation of CYP2D6 inactivation. 
      Accounting for MDMA depletion during the preincubation, corrected K(I) values 
      were significantly lower (0.11+/-0.05 microM, 0.15+/-0.09 microM, 0.24+/-0.16 
      microM for DF of 1.2, 5, and WR, respectively). Inactivation efficiency in 
      hepatocytes, as measured by k(inact)/K(I), was 10-fold less than that previously 
      reported in human liver microsomes or recombinantly expressed systems. Possible 
      causes for the observed differences between in vitro systems warrant further 
      investigation. These may include differences in metabolic consumption of MDMA in 
      each system, non-specific binding and presence of active efflux in hepatocytes.
FAU - Van, Linh M
AU  - Van LM
AD  - University of Sheffield, Academic Unit of Clinical Pharmacology, School of 
      Medicine, Sheffield S10 2JF, UK.
FAU - Swales, John
AU  - Swales J
FAU - Hammond, Clare
AU  - Hammond C
FAU - Wilson, Claire
AU  - Wilson C
FAU - Hargreaves, Judith A
AU  - Hargreaves JA
FAU - Rostami-Hodjegan, Amin
AU  - Rostami-Hodjegan A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070220
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  - 04B7QNO9WS (Dextrorphan)
RN  - 7355X3ROTS (Dextromethorphan)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2D6)
RN  - ITX08688JL (Quinidine)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - Algorithms
MH  - Cell Count
MH  - Cell Survival/drug effects
MH  - Cryopreservation
MH  - Cytochrome P-450 CYP2D6/metabolism
MH  - *Cytochrome P-450 CYP2D6 Inhibitors
MH  - Dextromethorphan/metabolism
MH  - Dextrorphan/metabolism
MH  - Enzyme Inhibitors/metabolism/*pharmacology
MH  - Enzyme Stability/drug effects
MH  - Hepatocytes/cytology/*drug effects/enzymology
MH  - Humans
MH  - Kinetics
MH  - N-Methyl-3,4-methylenedioxyamphetamine/metabolism/*pharmacology
MH  - Quinidine/metabolism/pharmacology
MH  - Time Factors
EDAT- 2007/03/28 09:00
MHDA- 2007/07/17 09:00
CRDT- 2007/03/28 09:00
PHST- 2006/11/08 00:00 [received]
PHST- 2007/02/04 00:00 [revised]
PHST- 2007/02/15 00:00 [accepted]
PHST- 2007/03/28 09:00 [pubmed]
PHST- 2007/07/17 09:00 [medline]
PHST- 2007/03/28 09:00 [entrez]
AID - S0928-0987(07)00046-2 [pii]
AID - 10.1016/j.ejps.2007.02.005 [doi]
PST - ppublish
SO  - Eur J Pharm Sci. 2007 May;31(1):53-61. doi: 10.1016/j.ejps.2007.02.005. Epub 2007 
      Feb 20.