Inhibition of cytochrome P450 by nefazodone in vitro: Studies of dextromethorphan O- and N-demethylation

被引:45
作者
Schmider, J
Greenblatt, DJ
VonMoltke, LL
Harmatz, JS
Shader, RI
机构
[1] Dept. Pharmacol. and Exp. Therapeut., Tufts University, School of Medicine, Boston, MA
[2] Dept. Pharmacol. and Exp. Therapeut., Tufts University, School of Medicine, Boston MA 02111
关键词
nefazodone; in vitro; human liver microsomes; CYP3A3/4; CYP2D6; cytochrome P450; dextromethorphan;
D O I
10.1046/j.1365-2125.1996.30512.x
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Nefazodone (NEF), a 5-HT2A/2C antagonist antidepressant, is extensively metabolized in the human body to hydroxy NEF (OH-NEF), p-hydroxy NEF (pOH-NEF), a dione metabolite, and via cleavage of the molecule to m-chlorophenyl-piperazine (mCPP) and BMY-33604. The latter is further metabolized to BMS-183695-01 (BMSa) and EMS-183562-01 (BMSb). To investigate the potential of NEF and its metabolites to interfere with the metabolism of other drugs, we tested these compounds for their ability to alter dextromethorphan (DMO) O-demethylation to dextrorphan (DOP; an index reaction for CYP2D6) and N-demethylation to 3-methoxy morphinan (MEM, a recently proposed index reaction of CYP3A3/4), The assay was performed in an in vitro system with human liver microsomes from three different donors. NEF, OH-NEF, pOH-NEF, mCPP and BMSb were weak inhibitors of DMO O and N-demethylation, with average K-i values ranging from 18 to 50 mu M for DOP formation, and from 21 to > 200 mu M for MEM formation. The dione metabolite and BMSa did not produce detectable inhibition of either pathway. The findings for DMO O-demethylation, well-established as a CYP2D6-mediated reaction, indicate that NEF and metabolites are weak inhibitors of this reaction, with K-i values at least 100 times higher than fluoxetine (K-i = 0.1 mu M +/- 0.09). The implications of results on DMO N-demethylation are not clear. In vivo data, as well as in vitro data based on 'pure' CYP3A3/4 substrates, provide evidence for clinically relevant CYP3A3/4 inhibition by NEF, OH-NEF, and pOH-NEF. Thus, formation of MEM by N-demethylation of DMO may not constitute a suitable index reaction to probe CYP3A3/4 activity.
引用
收藏
页码:339 / 343
页数:5
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