INHIBITION OF CYTOCHROME-P450 BY NEFAZODONE IN-VITRO - STUDIES OF DEXTROMETHORPHAN O-DEMETHYLATION AND N-DEMETHYLATION

Nefazodone (NEF), a 5-HT2A/2C antagonist antidepressant, is extensivel y 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 me tabolized to BMS-183695-01 (BMSa) and EMS-183562-01 (BMSb). To investi gate the potential of NEF and its metabolites to interfere with the me tabolism of other drugs, we tested these compounds for their ability t o 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 inhib itors of DMO O and N-demethylation, with average K-i values ranging fr om 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 in hibition of either pathway. The findings for DMO O-demethylation, well -established as a CYP2D6-mediated reaction, indicate that NEF and meta bolites 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 impli cations 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.