The Role of Metabolic Activation in Drug-Induced Hepatotoxicity

Park, B. Kevin; Kitteringham, Neil R.; Maggs, James L.; Pirmohamed, Munir; Williams, Dominic P.

doi:10.1146/annurev.pharmtox.45.120403.100058

Cited by 416 publications

(301 citation statements)

References 92 publications

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“…Taken together, these findings strongly suggest that the difference in AUC between radioactivity and osimertinib, AZ5104, and AZ7550 is due to osimertinib-related material bound to plasma proteins, especially albumin. No findings in the clinical or preclinical studies to date indicate that covalent binding of osimertinib and/or its metabolites to proteins is associated with any toxicologic sequelae, such as idiosyncratic liver or immune-mediated toxicity (Zhou et al, 2005;Park et al, 2005). In humans, the most abundant circulating metabolites observed in steady-state plasma extracts from patients dosed with non-radiolabeled osimertinib at 80 mg were AZ5104 (N-demethylation on the indole) and AZ7550 (N-demethylation on the dimethyl amine), representing 8% and 6% of total drug-related material, respectively.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Disposition of Osimertinib in Rats, Dogs, and Humans: Insights into a Drug Designed to Bind Covalently to a Cysteine Residue of Epidermal Growth Factor Receptor

Dickinson

Cantarini

Collier

et al. 2016

Drug Metabolism and Disposition

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Preclinical and clinical studies were conducted to determine the metabolism and pharmacokinetics of osimertinib and key metabolites AZ5104 and AZ7550. Osimertinib was designed to covalently bind to epidermal growth factor receptors, allowing it to achieve nanomolar cellular potency . Covalent binding was observed in incubations of radiolabeled osimertinib with human and rat hepatocytes, human and rat plasma, and human serum albumin. Osimertinib, AZ5104, and AZ7550 were predominantly metabolized by CYP3A. Seven metabolites were detected in human hepatocytes, also observed in rat or dog hepatocytes at similar or higher levels. After oral administration of radiolabeled osimertinib to rats, drug-related material was widely distributed, with the highest radioactivity concentrations measured at 6 hours postdose in most tissues; radioactivity was detectable in 42% of tissues 60 days postdose. Concentrations of [ 14 C]-radioactivity in blood were lower than in most tissues. After the administration of a single oral dose of 20 mg of radiolabeled osimertinib to healthy male volunteers, ∼19% of the dose was recovered by 3 days postdose. At 84 days postdose, mean total radioactivity recovery was 14.2% and 67.8% of the dose in urine and feces. The most abundant metabolite identified in feces was AZ5104 (∼6% of dose). Osimertinib accounted for ∼1% of total radioactivity in the plasma of non-small cell lung cancer patients after 22 days of 80-mg osimertinib once-daily treatment; the most abundant circulatory metabolites were AZ7550 and AZ5104 (<10% of total osimertinibrelated material). Osimertinib is extensively distributed and metabolized in humans and is eliminated primarily via the fecal route.

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Section: Discussionmentioning

confidence: 99%

Metabolic Disposition of Osimertinib in Rats, Dogs, and Humans: Insights into a Drug Designed to Bind Covalently to a Cysteine Residue of Epidermal Growth Factor Receptor

Dickinson

Cantarini

Collier

et al. 2016

Drug Metabolism and Disposition

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“…[50][51][52] Doxorubicin and tamoxifen are cancer chemotherapeutics and have been cited for in vivo and in vitro hepatoxicities, presumably due to oxidative stress. 53,54 Methylmercury chloride, phenylmercuric acetate, and mercury chloride are mercury-containing compounds that have been well established as an environmental toxins and public health risks. 55,56 Despite the fact that no definitive primary mechanism of toxicity has been reported, a range of potential mechanisms have been proposed, such as mitochondrial dysfunction, lipid peroxidation, microtubule disruption, and oxidative stress.…”

Section: Cytotoxicity Of Chemical Compoundsmentioning

confidence: 99%

Assessment of Compound Hepatotoxicity Using Human Plateable Cryopreserved Hepatocytes in a 1536-Well-Plate Format

Moeller¹,

Shukla

Xia

2012

ASSAY and Drug Development Technologies

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Hepatotoxicity is a major concern for both drug development and toxicological evaluation of environmental chemicals. The assessment of compound-induced hepatotoxicity has traditionally relied on in vivo testing; however, it is being replaced by human in vitro models due to an emphasis on the reduction of animal testing and species-specific differences. Since most cell lines and hybridomas lack the full complement of enzymes at physiological levels found in the liver, primary hepatocytes are the gold standard to study liver toxicities in vitro due to the retention of most of their in vivo activities. Here, we optimized a cell viability assay using plateable cryopreserved human hepatocytes in a 1536-well-plate format. The assay was validated by deriving inhibitory concentration at 50% values for 12 known compounds, including tamoxifen, staurosporine, and phenylmercuric acetate, with regard to hepatotoxicity and general cytotoxicity using multiple hepatocyte donors. The assay performed well, and the cytotoxicity of these compounds was confirmed in comparison to HepG2 cells. This is the first study to report the reliability of using plateable cryopreserved human hepatocytes for cytotoxicity studies in a 1536-well-plate format. These results suggest that plateable cryopreserved human hepatocytes can be scaled up for screening a large compound library and may be amenable to other hepatocytic assays such as metabolic or drug safety studies.

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“…1999; Boelsterli 2003; Park et al. 2005). In addition, diclofenac is able to induce direct mitochondrial dysfunction (Begriche et al.…”

Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

181

154

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Drug‐induced toxicity is a key issue for public health because some side effects can be severe and life‐threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug‐induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug‐induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug‐induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.

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The Role of Metabolic Activation in Drug-Induced Hepatotoxicity

Cited by 416 publications

References 92 publications

Metabolic Disposition of Osimertinib in Rats, Dogs, and Humans: Insights into a Drug Designed to Bind Covalently to a Cysteine Residue of Epidermal Growth Factor Receptor

Metabolic Disposition of Osimertinib in Rats, Dogs, and Humans: Insights into a Drug Designed to Bind Covalently to a Cysteine Residue of Epidermal Growth Factor Receptor

Assessment of Compound Hepatotoxicity Using Human Plateable Cryopreserved Hepatocytes in a 1536-Well-Plate Format

Role of endoplasmic reticulum stress in drug‐induced toxicity

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