Combination of GSH Trapping and Time-Dependent Inhibition Assays as a Predictive Method of Drugs Generating Highly Reactive Metabolites

Nakayama, S.; Takakusa, Hideo; Watanabe, Akïharu; Miyaji, Yoshihiro; Suzuki, Wataru; Sugiyama, Daisuke; Shiosakai, Kazuhito; Honda, Kokichi; Okudaira, Noriko; Izumi, Tohru; Okazaki, Osamu

doi:10.1124/dmd.111.039180

Cited by 26 publications

(20 citation statements)

References 47 publications

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“…M14 and M17 were probably formed from GSH substitution of M2 and M7, respectively. The evidence of GSH substitution could suggest potential covalent binding of BIIB021 or its metabolites to endogenous proteins (Nakayama et al, 2011). After incubation of [ 14 C]BIIB021 with hepatocytes, the recovery of radioactivity was greater than 85%, indicating that the covalent protein binding potential may be lower than 15% and GSH may play an important role in protecting against undesired covalent binding of endogenous proteins.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Metabolism of BIIB021, an Inhibitor of Heat Shock Protein 90, in Liver Microsomes and Hepatocytes of Rats, Dogs, and Humans and Recombinant Human Cytochrome P450 Isoforms

Xu¹,

Woodward²,

Khan³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Inhibition of heat shock protein 90 (HSP90) results in the degradation of oncoproteins that drive malignant progression and induce cell death, thus making HSP90 a potential target of cancer therapy. 6-Chloro-9-(4-methoxy-3, 5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine (BIIB021), a synthetic HSP90 inhibitor, exhibited promising antitumor activity in preclinical models. It is currently in phase II clinical trials for the oral treatment of breast cancer. The objective of this study was to obtain both quantitative and qualitative metabolic profiles of

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Section: Discussionmentioning

confidence: 99%

In Vitro Metabolism of BIIB021, an Inhibitor of Heat Shock Protein 90, in Liver Microsomes and Hepatocytes of Rats, Dogs, and Humans and Recombinant Human Cytochrome P450 Isoforms

Xu¹,

Woodward²,

Khan³

et al. 2012

Drug Metab Dispos

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“…In this work, the identification of covalent adducts by GSH trapping was adopted. GSH acted as a trapping agent to identify the structure of RMs [29], and this classical approach is widely employed in the detection of RMs [30]. A comprehensive understanding of the fragmentation behavior of GSH [31] was helpful for analyzing the behavior of GSH-myristicin adducts.…”

Section: Gsh Capture Of the Reactive Metabolitesmentioning

confidence: 99%

Identification and characterization of reactive metabolites in myristicin-mediated mechanism-based inhibition of CYP1A2

Yang

Chen

et al. 2015

Chemico-Biological Interactions

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“…This leads metabolite analysis to be performed only for diagnosing an idiosyncratic event rather than determining its severity. For reactive metabolite counts, GSH trapping can be used to quantify the level of oxidative metabolites before being run through HPLC and MS [144]. Additionally, adduct formation of proteins can also be measured using LC-MS, providing insight towards the mechanism of injury [117, 145].…”

Section: Assays Detecting Susceptibility For Idiosyncratic Reactionsmentioning

confidence: 99%

Idiosyncratic Drug-Induced Liver Injury (IDILI): Potential Mechanisms and Predictive Assays

Roth

Lee

2017

BioMed Research International

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Idiosyncratic drug-induced liver injury (IDILI) is a significant source of drug recall and acute liver failure (ALF) in the United States. While current drug development processes emphasize general toxicity and drug metabolizing enzyme- (DME-) mediated toxicity, it has been challenging to develop comprehensive models for assessing complete idiosyncratic potential. In this review, we describe the enzymes and proteins that contain polymorphisms believed to contribute to IDILI, including ones that affect phase I and phase II metabolism, antioxidant enzymes, drug transporters, inflammation, and human leukocyte antigen (HLA). We then describe the various assays that have been developed to detect individual reactions focusing on each of the mechanisms described in the background. Finally, we examine current trends in developing comprehensive models for examining these mechanisms. There is an urgent need to develop a panel of multiparametric assays for diagnosing individual toxicity potential.

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Combination of GSH Trapping and Time-Dependent Inhibition Assays as a Predictive Method of Drugs Generating Highly Reactive Metabolites

Abstract: ABSTRACT:Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as

Cited by 26 publications

References 47 publications

In Vitro Metabolism of BIIB021, an Inhibitor of Heat Shock Protein 90, in Liver Microsomes and Hepatocytes of Rats, Dogs, and Humans and Recombinant Human Cytochrome P450 Isoforms

In Vitro Metabolism of BIIB021, an Inhibitor of Heat Shock Protein 90, in Liver Microsomes and Hepatocytes of Rats, Dogs, and Humans and Recombinant Human Cytochrome P450 Isoforms

Identification and characterization of reactive metabolites in myristicin-mediated mechanism-based inhibition of CYP1A2

Idiosyncratic Drug-Induced Liver Injury (IDILI): Potential Mechanisms and Predictive Assays

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