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Detection of novel reactive metabolites of trazodone: evidence for CYP2D6-mediated bioactivation of m-chlorophenylpiperazine.
Drug Metab Dispos. 2008 May; 36(5):841-50.DM

Abstract

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.

Links

Publisher Full Text (DOI)

Authors+Show Affiliations

Wen B
Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey, USA. bo.wen@roche.com
Ma L
No affiliation info available
Rodrigues AD
No affiliation info available
Zhu M
No affiliation info available

MeSH

Antidepressive Agents, Second-GenerationBiotransformationCytochrome P-450 CYP2D6GlutathioneHumansMicrosomes, LiverPiperazinesRecombinant ProteinsSerotonin Receptor AgonistsTrazodone

Pub Type(s)

Journal Article

Language

eng

PubMed ID

18238857

Citation

Wen, Bo, et al. "Detection of Novel Reactive Metabolites of Trazodone: Evidence for CYP2D6-mediated Bioactivation of M-chlorophenylpiperazine." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 36, no. 5, 2008, pp. 841-50.
Wen B, Ma L, Rodrigues AD, et al. Detection of novel reactive metabolites of trazodone: evidence for CYP2D6-mediated bioactivation of m-chlorophenylpiperazine. Drug Metab Dispos. 2008;36(5):841-50.
Wen, B., Ma, L., Rodrigues, A. D., & Zhu, M. (2008). Detection of novel reactive metabolites of trazodone: evidence for CYP2D6-mediated bioactivation of m-chlorophenylpiperazine. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 36(5), 841-50. https://doi.org/10.1124/dmd.107.019471
Wen B, et al. Detection of Novel Reactive Metabolites of Trazodone: Evidence for CYP2D6-mediated Bioactivation of M-chlorophenylpiperazine. Drug Metab Dispos. 2008;36(5):841-50. PubMed PMID: 18238857.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Detection of novel reactive metabolites of trazodone: evidence for CYP2D6-mediated bioactivation of m-chlorophenylpiperazine. AU - Wen,Bo, AU - Ma,Li, AU - Rodrigues,A David, AU - Zhu,Mingshe, Y1 - 2008/01/31/ PY - 2008/2/2/pubmed PY - 2008/8/19/medline PY - 2008/2/2/entrez SP - 841 EP - 50 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 36 IS - 5 N2 - 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. SN - 1521-009X UR - https://www.unboundmedicine.com/medline/citation/18238857/Detection_of_novel_reactive_metabolites_of_trazodone:_evidence_for_CYP2D6_mediated_bioactivation_of_m_chlorophenylpiperazine_ DB - PRIME DP - Unbound Medicine ER -