RT Journal Article
SR Electronic
T1 Detection of Novel Reactive Metabolites of Trazodone: Evidence for CYP2D6-Mediated Bioactivation of <em>m</em>-Chlorophenylpiperazine
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 841
OP 850
DO 10.1124/dmd.107.019471
VO 36
IS 5
A1 Bo Wen
A1 Li Ma
A1 A. David Rodrigues
A1 Mingshe Zhu
YR 2008
UL http://dmd.aspetjournals.org/content/36/5/841.abstract
AB Several new glutathione adducts (M3–M7) of trazodone were tentatively identified in human liver microsomal incubations using liquid chromatography-tandem mass spectrometry (LC/MS/MS). Following incubations with trazodone in the presence of glutathione, 1-(3′-chlorophenyl)piperazine (m-CPP), a major circulating and pharmacologically active metabolite of several antidepressants including trazodone, nefazodone, and etoperidone, was trapped with glutathione to afford the corresponding quinone imine-sulfydryl adducts M4 and M5. Two novel glutathione adducts of deschloro-m-CPP and deschloro-trazodone, M3 and M6, were also detected by tandem mass spectrometry. The identities of these m-CPP-derived glutathione adducts were further confirmed by LC/MS/MS analyses of microsomal incubations of m-CPP. To investigate the bioactivation mechanism, a regioisomer of m-CPP, 1-(4′-chlorophenyl)piperazine, was incubated in human liver microsomes. Blockage of bioactivation by 4′-chloro-substitution at least partially suggested that formation of m-CPP-derived glutathione adducts M3, M4, and M5 is mediated by a common quinone imine intermediate. A tentative pathway states that upon formation of the trazodone- and m-CPP-1′,4′-quinone imine intermediates through initial 4′-hydroxylation, glutathione attacks at the chlorine position by an ipso substitution, resulting in 4′-hydroxy-3′-glutathion-deschloro-trazodone (M6) and 4′-hydroxy-3′-glutathion-deschloro-m-CPP (M3), respectively. In contrast to CYP3A4-dependent bioactivation of trazodone itself, formation of M4 was mediated specifically by CYP2D6, as evidenced by cDNA-expressed CYP2D6-catalyzing formation of M4 from m-CPP, strong inhibition of formation of M4 by quinidine, a specific CYP2D6 inhibitor, in both incubations of trazodone and m-CPP with human liver microsomes, and concentration-dependent inhibition of M4 formation by quinidine. The American Society for Pharmacology and Experimental Therapeutics