Inhibition of cytochrome P450 by nefazodone in vitro: studies of dextromethorphan O‐ and N‐demethylation

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Abstract
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 BMS‐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 Ki values ranging from 18 to 50 μm for DOP formation, and from 21 to >200 μm 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 Ki values at least 100 times higher than fluoxetine (Ki=0.1 μm±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.

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