Drug-Induced Liver Injury

Hamilton, Leslie A.; Collins‐Yoder, Angela; Collins, Rachel

doi:10.4037/aacnacc2016953

Cited by 33 publications

(19 citation statements)

References 167 publications

(149 reference statements)

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“…This section summarizes the toxic biomarkers used in in vitro models (Table 1). AST (aspartate aminotransferase) [19] Diagnostic marker of liver damage √ ALP (alkalinephosphatase) [19] Diagnostic marker of cholestatic injury √ GLDH (glutamate dehydrogenase) [20] Early detection biomarker ×…”

Section: Biomarkers For Drug Toxicity Testingmentioning

confidence: 99%

Drug Toxicity Evaluation Based on Organ-on-a-chip Technology: A Review

Han

Wang

et al. 2020

Micromachines

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Organ-on-a-chip academic research is in its blossom. Drug toxicity evaluation is a promising area in which organ-on-a-chip technology can apply. A unique advantage of organ-on-a-chip is the ability to integrate drug metabolism and drug toxic processes in a single device, which facilitates evaluation of toxicity of drug metabolites. Human organ-on-a-chip has been fabricated and used to assess drug toxicity with data correlation with the clinical trial. In this review, we introduced the microfluidic chip models of liver, kidney, heart, nerve, and other organs and multiple organs, highlighting the application of these models in drug toxicity detection. Some biomarkers of toxic injury that have been used in organ chip platforms or have potential for use on organ chip platforms are summarized. Finally, we discussed the goals and future directions for drug toxicity evaluation based on organ-on-a-chip technology.

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Section: Biomarkers For Drug Toxicity Testingmentioning

confidence: 99%

Drug Toxicity Evaluation Based on Organ-on-a-chip Technology: A Review

Han

Wang

et al. 2020

Micromachines

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“…The liver is a vital organ which plays a key role in detoxifying various drugs and xenobiotic compounds (Shati, 2014a). The liver is commonly damaged by many toxic and chemical substances, one among them is NSAIDS (Hamilton et al, 2016). NSAIDS are commonly used for the treatment of many acute and chronic in lammatory conditions, pain management, rheumatic disorder and ankylosing spondylosis (Vuppalanchi et al, 2007) (Skoutakis et al, 1988.…”

Section: Introductionmentioning

confidence: 99%

Antioxidant effects of vitamin E on diclofenac induced hepatotoxicity in male rats

Siva¹,

Sivakumar²,

Pk³

et al. 2019

ijrps

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Drug induced liver injury possesses a major clinical problem and has become leading cause of acute liver failure and transplantation. Overstressed liver compromises its detoxification role which may expose it to a variety of diseases and disorders. The present study was to determine whether pre- administration of various doses of vitamin E would have protective effect against diclofenac induced hepatotoxicity in wistar male rats. Twenty-four albino male rats weighing 180-200g were divided equally into four groups. In control group rats were administrated with physiological saline 2ml/kg b.wt /intramuscularly. Another group with 50mg/kg b.wt/ intramuscularly/seven days diclofenac was used for inducing toxicity. In experimental groups rats were administrated with different doses of vitamin E along with diclofenac sodium [200 and 400 IU orally and 50mg/kg b.wt/ intramuscularly/seven days]. Showed that there was a rapid increase in the levels of liver function test in diclofenac treated group, which was significantly decreased after pre-treatment with high dose than low dose of vitamin E. The liver acinus showed Centro acinar necrosis of hepatocytes after 7 days of diclofenac treatment, which was prevented by administration of Vitamin E. Drug-induced liver injury possesses a major clinical problem and has become a leading cause of acute liver failure and transplantation. Overstressed liver compromises its detoxification role which may expose it to a variety of diseases and disorders. Diclofenac sodium is a phenylacetic acid derivative, a widely used nonsteroidal anti-inflammatory drug (NSAID) for the treatment of inflammatory conditions such as osteoarthritis, rheumatoid arthritis, polymyositis, dermatomyositis, dental pain, spondyloarthritis, acute migraine, gout attacks and pain management in gall and renal stones. Although the exact mechanism by with diclofenac injuries liver is not understood, some studies explain the toxicity by affecting cytochrome P 450 leading to the production of active metabolites. Administration of different dose of diclofenac sodium induces severe adverse effects in liver and kidney.

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“…Due to this enormous medical relevance, the detection of DILI at an early stage would be highly beneficial, both for a duly termination of treatment with the DILI-causing compound as well as for an early start of therapeutic interventions with curative counteragents. Manifestations of DILI can be differentiated in hepatocellular DILI, cholestatic DILI where cellular damage of the hepatocytes or of the cholangiocytes is the predominant injury, respectively, or a mixture of both (Hamilton et al 2016). For the categorisation of DILI, current regulatory diagnosis guidelines assess the relative increase in blood plasma levels of the enzymes alanine transferase (ALT) and alkaline phosphatase (ALP).…”

Section: Introductionmentioning

confidence: 99%

A physiology-based model of bile acid metabolism shows altered tissue concentrations after drug administration and in specific genotype subgroups

Baier

Cordes

Thiel

et al. 2018

Preprint

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Drug-induced liver injuries (DILI) are an important issue in drug development and patient safety and often lead to termination of drug-development programs or late withdrawals of drugs. Since DILI events are hard to diagnose in preclinical settings, a need for alternative prediction methods such as computational modeling emerges. Impairment of bile acid (BA) metabolism, known as cholestasis, is a frequent form of DILI. Being rather a systemic then a single organ related disease, whole-body physiology-based modeling is a predestined approach for cholestasis modeling. The objectives of the presented study were 1) the development of a physiology-based model for human bile acid metabolism, 2) model validation and characterization for a virtual population, and 3) prediction and quantification of the effects of genetic predispositions and drug interaction on bile acid metabolism. The developed physiology-based bile acid (PBBA) model is based on the standard PBPK model of PKSim® and describes the bile acid circulation in a healthy reference individual. Active processes such as the hepatic synthesis, gallbladder emptying upon meal intake, transition through the gastrointestinal tract, reabsorption into the liver, distribution within the body, and excretion are included. The kinetics of active processes for the surrogate BA glycochenodeoxycholic acid were fitted to time-concentration profiles of blood BA levels reported in literature. The robustness of our PBBA model is underlined by the comparison of simulated plasma BA concentrations in a virtual population of 1,000 healthy individuals with reported data. In addition to plasma concentrations, the PBBA model allows simulations of BA exposure in relevant tissues like the liver and can therefore enhance the mechanistic understanding of cholestasis. This feature was used to analyse the reported increased risk of cholestatic DILI in Benign Recurrent Intrahepatic Cholestasis type 2 (BRIC2) patients. Simulations of the PBBA model suggest a higher susceptibility of BRIC2 patients towards cholestatic DILI due to BA accumulation in hepatocytes. Apart from these intrinsic effects, drug-interactions and their effect on the systemic bile acid metabolism were simulated by combining the PBBA model with a drug PBPK model of cyclosporine A (CsA). The results of which confirmed the reported higher risk of developing DILI as a consequence of CsA intake. Altogether, the presented model enhances our mechanistic understanding of cholestasis, allows the identification of drug-interactions leading to altered BA levels in blood and organs, and could be used to prevent clinical cases of cholestasis and enhance patient safety.

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Drug-Induced Liver Injury

Cited by 33 publications

References 167 publications

Drug Toxicity Evaluation Based on Organ-on-a-chip Technology: A Review

Drug Toxicity Evaluation Based on Organ-on-a-chip Technology: A Review

Antioxidant effects of vitamin E on diclofenac induced hepatotoxicity in male rats

A physiology-based model of bile acid metabolism shows altered tissue concentrations after drug administration and in specific genotype subgroups

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