title: Human CYP3A4 and the metabolism of nefazodone and hydroxynefazodone by human liver microsomes and heterologously expressed enzymes.
abstract: Nefazodone is an antidepressant with a relatively unique structure and mechanism of action. The current study was conducted to assess the potential for nefazodone to have metabolic drug interactions associated with cytochrome P450 (CYP) enzymes. Nefazodone is metabolised to hydroxynefazodone (OH-NEF), triazoledione (TD), and m-chlorophenylpiperazine (m-CPP), and OH-NEF is metabolised to TD and m-CPP. Correlations with enzyme activities in a panel of microsomes prepared from human livers, incubations with heterologously expressed human CYP enzymes, and incubations with enzyme inhibitors were used to study these metabolic pathways. The results suggest that the metabolism of NEF and OH-NEF to each of their active metabolites is catalysed mainly by CYP3A4, which is in agreement with clinical reports of drug--drug interactions of nefazodone with substrates and inhibitors of CYP3A4.
authors.affiliation: Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada T6G 2B7. susan_rotzinger@camh.net
authors.forename: Susan
authors.initials: S
authors.lastname: Rotzinger
authors.forename: Glen B
authors.initials: GB
authors.lastname: Baker
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000737:chemistry / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007313:Insecta; D007654:Ketoconazole / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D010879:Piperazines; D014162:Transfection; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D018687:Antidepressive Agents, Second-Generation; D065607:Cytochrome P-450 Enzyme Inhibitors; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D010879:Piperazines; D014230:Triazoles; C092333:hydroxynefazodone; C051752:nefazodone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole