The antidepressant nefazodone (NFZ) determined several cases of acute hepatotoxicity/liver failure. Since the mechanism of hepatotoxicity still remains unknown, NFZ and two of its main metabolites, triazoledione (TZL) and m-chlorophenylpiperazine (mCPP), have been studied for their cytochrome P450 inhibition and cytotoxicity on human hepatocytes. Trazodone (TZD) was also investigated since it shares with nefazodone the mCPP metabolite. The inhibitory activity on recombinant human cytochrome

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... isoforms (CYP1A2, CYP2A6, CYP3A4, CYP2C8, CYP2C9 and CYP2D6) was determined by a fluorimetric assay wereas cytotoxicity was tested on human hepatocytes primary cultures. NFZ strongly inhibited CYP 3A4 (IC50 = 1.55 µM) and to a lesser extent CYP 2C9 (IC50 = 5.13 µM). A weak inhibition on CYP 2D6 was exerted by TZD, NFZ and m-CPP (IC50 = 29 µM, 20 µM and 7.78 µM, respectively) while only m-CPP weakly inhibited CYP 2A6 (IC50 = 10 µM). In human hepatocytes primary cultures NFZ resulted highly cytotoxic (IC50 = 44.35 µM and 27.78 µM after 24h and 48h, respectively). On the contrary, TZD and mCPP showed very low cytotoxicity (IC50 ≈ 400 µM) as well as TZL (IC50 > 800 µM). In conclusion, the present study demonstrates that NFZ is a strong inhibitor of the cytochrome P450 isoenzyme CYP 3A4 and highly cytotoxic on human hepatocytes, while no relevant cytochrome P450 inhibition or cytotoxic effects on human hepatocytes could be ascribed to its metabolites TZL and m-CPP and to the antidepressant drug TZD.