Nefazodone metabolites oxidative

Nefazodone is a phenylpiperazine antidepressant structurally related to trazodone, but it differs pharmacologically from trazodone, the SSRIs, the MAOIs, and the TCAs (Fig. 21.22). When compared with trazodone, nefazodone displays approximately twice the affinity potency for SERT. Nefazodone therapy, however, was associated with life-threatening cases of idiosyncratic hepatotoxicity, and as a result, nefazodone was withdrawn from both the North American and European markets in 2003. The mechanism of hepatotoxicity remains unknown, but nefazodone, being structurally similar to trazodone (Fig. 21.23), is metabolized to p-hydroxynefazodone, m-CPP, and phenoxyethyltriazoledione. In turn, p-hydroxynefazodone is thought to be oxidized to an iminoquinone and/or an epoxide reactive metabolite, which may play a role in the initiation of nefazodone-mediated hepatotoxicity (76). 

Ketoconazoie is reported to increase the peak plasma levels and AUC of mirtazapine by about 30% and 45%, respectively. Mirtazapine is extensively metabolised and the cytochrome P450 isoenzyme CYP3A4 is thought to be responsi ble for the formation of the N-demethy 1 and N-oxide metabolites. The manufacturers advise caution when potent inhibitors of CYP3A4 such as azole antifungals, protease inhibitors, erythromycin, or nefazodone are given with mirtazapine. ... 

---