PMID- 10445380
OWN - NLM
STAT- MEDLINE
DCOM- 19990914
LR  - 20190726
IS  - 0033-3158 (Print)
IS  - 0033-3158 (Linking)
VI  - 145
IP  - 1
DP  - 1999 Jul
TI  - Nefazodone, meta-chlorophenylpiperazine, and their metabolites in vitro: 
      cytochromes mediating transformation, and P450-3A4 inhibitory actions.
PG  - 113-22
AB  - RATIONALE: Understanding of the mechanisms of biotransformation of antidepressant 
      drugs, and of their capacity to interact with other medications, is of direct 
      relevance to rational clinical psychopharmacology. OBJECTIVES: To determine the 
      human cytochromes P450 mediating the metabolism of nefazodone, and the inhibitory 
      activity of nefazodone and metabolites versus human P450-3A. METHODS: 
      Biotransformation of nefazodone to its metabolic products, and of 
      meta-chlorophenylpiperazine (mCPP) to para-hydroxy-mCPP, was studied in vitro 
      using human liver microsomes and heterologously expressed human cytochromes. 
      Nefazodone and metabolites were also tested as inhibitors of alprazolam 
      hydroxylation, reflecting activity of cytochrome P450-3A isoforms. RESULTS: mCPP 
      and two hydroxylated derivatives were the principal metabolites formed from 
      nefazodone by liver microsomes. Metabolite production was strongly inhibited by 
      ketoconazole or troleandomycin (relatively specific P450-3A inhibitors), and by 
      an anti-P450-3A antibody. Only heterologously expressed human P450-3A4 mediated 
      formation of nefazodone metabolites from the parent compound. Nefazodone, 
      hydroxy-nefazodone, and para-hydroxy-nefazodone were strong 3A inhibitors, being 
      more potent than norfluoxetine and fluvoxamine, but less potent than 
      ketoconazole. The triazoledione metabolite and mCPP had weak or negligible 
      3A-inhibiting activity. Formation of parahydroxy-mCPP from mCPP was mediated by 
      heterologously expressed P450-2D6; in liver microsomes, the reaction was strongly 
      inhibitable by quinidine, a relatively specific 2D6 inhibitor. CONCLUSION: The 
      complex parallel biotransformation pathways of nefazodone are mediated mainly by 
      human cytochrome P450-3A, whereas clearance of mCPP is mediated by P450-2D6. 
      Nefazodone and two of its hydroxylated metabolites are potent 3A inhibitors, 
      accounting for pharmacokinetic drug interactions of nefazodone with 3A substrate 
      drugs such as triazolam and alprazolam.
FAU - von Moltke, L L
AU  - von Moltke LL
AD  - Division of Clinical Pharmacology, New England Medical Center Hospital, Boston, 
      Massachusetts, USA. Lvonmoltke@Infonet.tufts.edu
FAU - Greenblatt, D J
AU  - Greenblatt DJ
FAU - Granda, B W
AU  - Granda BW
FAU - Grassi, J M
AU  - Grassi JM
FAU - Schmider, J
AU  - Schmider J
FAU - Harmatz, J S
AU  - Harmatz JS
FAU - Shader, R I
AU  - Shader RI
LA  - eng
GR  - DA-05258/DA/NIDA NIH HHS/United States
GR  - MH-19924/MH/NIMH NIH HHS/United States
GR  - MH-34223/MH/NIMH NIH HHS/United States
GR  - etc.
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - Germany
TA  - Psychopharmacology (Berl)
JT  - Psychopharmacology
JID - 7608025
RN  - 0 (Antidepressive Agents)
RN  - 0 (Piperazines)
RN  - 0 (Triazoles)
RN  - 59H4FCV1TF (nefazodone)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 1.- (Mixed Function Oxygenases)
RN  - EC 1.14.14.1 (CYP3A protein, human)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP3A)
RN  - REY0CNO998 (1-(3-chlorophenyl)piperazine)
RN  - YU55MQ3IZY (Alprazolam)
SB  - IM
MH  - Alprazolam/*pharmacokinetics
MH  - Antidepressive Agents/*pharmacokinetics
MH  - Biotransformation
MH  - Cytochrome P-450 CYP3A
MH  - Cytochrome P-450 Enzyme System/*metabolism
MH  - Drug Interactions
MH  - Humans
MH  - Hydroxylation/drug effects
MH  - Microsomes, Liver/*metabolism
MH  - Mixed Function Oxygenases/*metabolism
MH  - Piperazines/*pharmacokinetics
MH  - Triazoles/*pharmacokinetics
EDAT- 1999/08/13 00:00
MHDA- 1999/08/13 00:01
CRDT- 1999/08/13 00:00
PHST- 1999/08/13 00:00 [pubmed]
PHST- 1999/08/13 00:01 [medline]
PHST- 1999/08/13 00:00 [entrez]
AID - 10.1007/s002130051039 [doi]
PST - ppublish
SO  - Psychopharmacology (Berl). 1999 Jul;145(1):113-22. doi: 10.1007/s002130051039.