CPY3A4-Mediated <i>α</i>-Hydroxyaldehyde Formation in Saquinavir Metabolism

Li, Feng; Lu, Jie; Ma, Xiaochao

doi:10.1124/dmd.113.054874

Cited by 16 publications

(5 citation statements)

References 25 publications

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“…Therefore, the results were strongly empirical and dependent on the investigator’s level of knowledge. However, metabolomics-guided drug metabolism studies have not focused on specific metabolic pathways; therefore, this non-targeted approach facilitates the identification of novel metabolites, the characterization of metabolic enzymes, and the profiling of reactive metabolites [32,36,37,38,39,40,41,42]. This approach is complementary to conventional drug metabolism studies.…”

Section: Discussionmentioning

confidence: 99%

Revisiting the Metabolism and Bioactivation of Ketoconazole in Human and Mouse Using Liquid Chromatography–Mass Spectrometry-Based Metabolomics

Kim

Choi

Lee

et al. 2017

IJMS

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Although ketoconazole (KCZ) has been used worldwide for 30 years, its metabolic characteristics are poorly described. Moreover, the hepatotoxicity of KCZ limits its therapeutic use. In this study, we used liquid chromatography-mass spectrometry-based metabolomics to evaluate the metabolic profile of KCZ in mouse and human and identify the mechanisms underlying its hepatotoxicity. A total of 28 metabolites of KCZ, 11 of which were novel, were identified in this study. Newly identified metabolites were classified into three categories according to the metabolic positions of a piperazine ring, imidazole ring, and N-acetyl moiety. The metabolic characteristics of KCZ in human were comparable to those in mouse. Moreover, three cyanide adducts of KCZ were identified in mouse and human liver microsomal incubates as "flags" to trigger additional toxicity study. The oxidation of piperazine into iminium ion is suggested as a biotransformation responsible for bioactivation. In summary, the metabolic characteristics of KCZ, including reactive metabolites, were comprehensively understood using a metabolomics approach.

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Section: Discussionmentioning

confidence: 99%

Revisiting the Metabolism and Bioactivation of Ketoconazole in Human and Mouse Using Liquid Chromatography–Mass Spectrometry-Based Metabolomics

Kim

Choi

Lee

et al. 2017

IJMS

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“…In this study, we investigated the metabolic pathways of DLX in human liver microsomes (HLM) /mouse liver microsomes (MLM) and mice using liquid chromatography mass spectrometry (LC-MS)-based metabolomic approaches. Our previous studies demonstrated that LC-MS-based metabolomics is a rapid and effective approach to investigate drug metabolism ( Li et al, 2018 ; Li et al, 2020 ), bioactivation ( Li et al, 2011b ; Li et al, 2014 ; Liu et al, 2015 ; Liu et al, 2016 ; MacKenzie et al, 2020 ), and toxicity (O'Connell and Watkins, 2010; Li et al, 2013 ; Lu et al, 2019 ; Zhao et al, 2019 ). Here, a total of 39 metabolites generated from DLX were identified, of which 13 metabolites are novel.…”

Section: Introductionmentioning

confidence: 99%

Metabolism of a Selective Serotonin and Norepinephrine Reuptake Inhibitor Duloxetine in Liver Microsomes and Mice

et al. 2021

Self Cite

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Duloxetine (DLX) is a dual serotonin and norepinephrine reuptake inhibitor, widely used for the treatment of major depressive disorder. Although DLX has shown good efficacy and safety, serious adverse effects (e.g., liver injury) have been reported. The mechanisms associated with DLX-induced toxicity remain elusive. Drug metabolism plays critical roles in drug safety and efficacy. However, the metabolic profile of DLX in mice is not available, although mice serve as commonly used animal models for mechanistic studies of drug-induced adverse effects. Our study revealed 39 DLX metabolites in human/mouse liver microsomes and mice. Of note, 13 metabolites are novel, including five N -acetyl cysteine adducts and one reduced glutathione (GSH) adduct associated with DLX. Additionally, the species differences of certain metabolites were observed between human and mouse liver microsomes. CYP1A2 and CYP2D6 are primary enzymes responsible for the formation of DLX metabolites in liver microsomes, including DLX-GSH adducts. In summary, a total of 39 DLX metabolites were identified, and species differences were noticed in vitro. The roles of CYP450s in DLX metabolite formation were also verified using human recombinant cytochrome P450 (P450) enzymes and corresponding chemical inhibitors. Further studies are warranted to address the exact role of DLX metabolism in its adverse effects in vitro (e.g., human primary hepatocytes) and in vivo (e.g., Cyp1a2-null mice). SIGNIFICANCE STATEMENT This current study systematically investigated Duloxetine (DLX) metabolism and bioactivation in liver microsomes and mice. This study provided a global view of DLX metabolism and bioactivation in liver microsomes and mice, which are very valuable to further elucidate the mechanistic study of DLX-related adverse effects and drug-drug interaction from metabolic aspects.

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“…Drugs containing the benzylic carbon motif are prone to be oxidized to its corresponding benzylic alcohol (Mamidi et al, 2014;Ryu et al, 2014) and/or further to the end-product carboxylic acids in vivo (Hvenegaard et al, 2012;Walles et al, 2013;Pozo et al, 2015). It is recognized that there is an aldehyde intermediate in metabolic processing from alcohol to carboxylic acid, and some in vitro trapping tests with methoxyamine or semicarbazide also provided convincing evidence (Li et al, 2014;Inoue et al, 2015;Liu et al, 2015). However, further metabolism of aldehyde intermediates is rarely reported in publications.…”

Section: Discussionmentioning

confidence: 99%

Differences in the In Vivo and In Vitro Metabolism of Imrecoxib in Humans: Formation of the Rate-Limiting Aldehyde Intermediate

Hou

Zhou

et al. 2018

Drug Metab Dispos

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Imrecoxib is a typical cyclooxygenase-2 inhibitor and the benzylic carbon motif is its major site of oxidative metabolism, producing a hydroxymethyl metabolite (M1) and a carboxylic acid metabolite (M2). The plasma exposure of M2 is four times higher than those of both M0 and M1 in humans. However, this metabolite is rarely formed in in vitro experiments. Therefore, this study aims to investigate the formation mechanism of M2 and to further elucidate the reason for the discrepancy between in vitro and in vivo metabolic data. By employing human hepatocytes, human liver microsomes (HLMs), human liver cytosols (HLCs), recombinant enzymes, and selective enzyme inhibitors, the metabolic map of imrecoxib was elaborated as follows: the parent drug was initially hydroxylated to form M1 in HLMs, mainly mediated by CYP3A4 and CYP2D6, and to subsequently form aldehyde imrecoxib (M-CHO) in HLMs and HLCs. The latter process is the rate-limiting step in generating the end-product M2. In further M-CHO metabolism, two opposite reactions (namely, rapid oxidation catalyzed by CYP3A4, CYP2D6, and cytosolic aldehyde oxidase to form M2 versus reduction to regenerate M1 mediated by NADPH-dependent reductases in HLMs and HLCs, such as cytochrome P450 reductase) led to marked underestimation of the M2 amount in static in vitro incubations. The findings provided a possible explanation for the difference between in vitro and in vivo metabolism of imrecoxib, suggesting that the effect of competitive reduction on the static oxidation metabolism in in vitro metabolic experiments should be considered.

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CPY3A4-Mediated α-Hydroxyaldehyde Formation in Saquinavir Metabolism

Cited by 16 publications

References 25 publications

Revisiting the Metabolism and Bioactivation of Ketoconazole in Human and Mouse Using Liquid Chromatography–Mass Spectrometry-Based Metabolomics

Revisiting the Metabolism and Bioactivation of Ketoconazole in Human and Mouse Using Liquid Chromatography–Mass Spectrometry-Based Metabolomics

Metabolism of a Selective Serotonin and Norepinephrine Reuptake Inhibitor Duloxetine in Liver Microsomes and Mice

Differences in the In Vivo and In Vitro Metabolism of Imrecoxib in Humans: Formation of the Rate-Limiting Aldehyde Intermediate

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