Inhibition of cytochrome P450 by nefazodone in vitro: studies of dextromethorphan O- and N-demethylation.
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 microM for DOP formation, and from 21 to > 200 microM 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 microM +/- 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.
Schmider
J
J
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.
Greenblatt
D J
DJ
von Moltke
L L
LL
Harmatz
J S
JS
Shader
R I
RI
D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003917:Dextrorphan / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000187:drug effects; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D010090:Oxidoreductases, O-Demethylating / Q000378:metabolism; D010879:Piperazines; D014230:Triazoles / Q000494:pharmacology*
D018687:Antidepressive Agents, Second-Generation; D065607:Cytochrome P-450 Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D014230:Triazoles; D003917:Dextrorphan; C051752:nefazodone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010090:Oxidoreductases, O-Demethylating; C052861:dextromethorphan O-demethylase; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A