PMID- 17598095
OWN - NLM
STAT- MEDLINE
DCOM- 20080103
LR  - 20181201
IS  - 0031-6970 (Print)
IS  - 0031-6970 (Linking)
VI  - 63
IP  - 9
DP  - 2007 Sep
TI  - An in vitro approach to potential methadone metabolic-inhibition interactions.
PG  - 821-7
AB  - OBJECTIVE: The aim of this study was to assess the drug interaction potential of 
      psychotropic medication on methadone N-demethylation using cDNA-expressed 
      cytochrome P450 CYP enzymes. METHODS: Methadone was incubated with various drugs 
      (n = 10) and cDNA-expressed CYP3A4, CYP2D6, CYP2B6, CYP2C19 and CYP1A2 enzymes to 
      screen for their inhibition potency. The nature of enzyme selective activity for 
      inhibition was further investigated for potent inhibitors. To test for a 
      mechanism-based component in inhibition, all substances were tested with 
      preincubation and without. 2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine 
      (EDDP) concentration was determined by liquid chromatography/tandem mass 
      spectrometry following liquid/liquid extraction. RESULTS: Formation of EDDP was 
      catalysed by CYP3A4, CYP2D6 and CYP2C19. The N-demethylation of methadone was 
      preferentially inhibited by amitriptyline, buprenorphine, 
      methylenedioxymethamphetamine (MDMA) and zolpidem. Both amitriptyline and 
      buprenorphine were strong, reversible inhibitors of CYP3A4. Similarly, 
      amitriptyline and MDMA were identified as inhibitors of CYP2D6. Zolpidem revealed 
      a mechanism-based inhibition of CYP3A4. CONCLUSION: Amitriptyline, MDMA and 
      zolpidem are likely to slow down conversion of methadone and to increase its area 
      under the curve (AUC). A consideration of the in vitro evidence of drug-methadone 
      interactions should help to improve patient care during methadone maintenance 
      treatment.
FAU - Bomsien, Stephanie
AU  - Bomsien S
AD  - Institute of Legal Medicine and Traffic Medicine, Ruprecht-Karls University, 
      Vossstr. 2, 69115, Heidelberg, Germany.
FAU - Skopp, Gisela
AU  - Skopp G
LA  - eng
PT  - Journal Article
DEP - 20070628
PL  - Germany
TA  - Eur J Clin Pharmacol
JT  - European journal of clinical pharmacology
JID - 1256165
RN  - 0 (Analgesics, Opioid)
RN  - 0 (Cytochrome P-450 Enzyme Inhibitors)
RN  - 0 (Isoenzymes)
RN  - 0 (Propylamines)
RN  - 0 (Psychotropic Drugs)
RN  - 0 (Pyridines)
RN  - 0 (Pyrrolidines)
RN  - 0DHU5B8D6V (Citalopram)
RN  - 1806D8D52K (Amitriptyline)
RN  - 57WVB6I2W0 (Atomoxetine Hydrochloride)
RN  - 7K383OQI23 (Zolpidem)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 1.5.- (Oxidoreductases, N-Demethylating)
RN  - J60AR2IKIC (Clozapine)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
RN  - UC6VBE7V1Z (Methadone)
RN  - Z3LC48U94I (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine)
SB  - IM
MH  - Algorithms
MH  - Amitriptyline/metabolism/pharmacology
MH  - Analgesics, Opioid/metabolism/pharmacology
MH  - Atomoxetine Hydrochloride
MH  - Chromatography, Liquid/methods
MH  - Citalopram/metabolism/pharmacology
MH  - Clozapine/metabolism/pharmacology
MH  - Cytochrome P-450 Enzyme Inhibitors
MH  - Cytochrome P-450 Enzyme System/genetics/*metabolism
MH  - Dose-Response Relationship, Drug
MH  - Drug Interactions
MH  - Isoenzymes/antagonists & inhibitors/genetics/metabolism
MH  - Kinetics
MH  - Methadone/*metabolism/pharmacology
MH  - Methylation
MH  - N-Methyl-3,4-methylenedioxyamphetamine/metabolism/pharmacology
MH  - Oxidoreductases, N-Demethylating/antagonists & inhibitors/metabolism/pharmacology
MH  - Propylamines/metabolism/pharmacology
MH  - Psychotropic Drugs/metabolism/pharmacology
MH  - Pyridines/metabolism/pharmacology
MH  - Pyrrolidines/antagonists & inhibitors/metabolism
MH  - Tandem Mass Spectrometry/methods
MH  - Zolpidem
EDAT- 2007/06/29 09:00
MHDA- 2008/01/04 09:00
CRDT- 2007/06/29 09:00
PHST- 2007/05/02 00:00 [received]
PHST- 2007/05/22 00:00 [accepted]
PHST- 2007/06/29 09:00 [pubmed]
PHST- 2008/01/04 09:00 [medline]
PHST- 2007/06/29 09:00 [entrez]
AID - 10.1007/s00228-007-0327-z [doi]
PST - ppublish
SO  - Eur J Clin Pharmacol. 2007 Sep;63(9):821-7. doi: 10.1007/s00228-007-0327-z. Epub 
      2007 Jun 28.