Role of the Adaptive Immune System in Idiosyncratic Drug-Induced Liver Injury

Uetrecht, Jack

doi:10.1016/b978-0-12-387817-5.00011-x

Cited by 5 publications

(4 citation statements)

References 140 publications

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“…Difficulties in the detection of hypersensitivity reactions and idiosyncratic toxicities arise due to ADR events that often occur already at low therapeutic dose levels in only small numbers of individuals during clinical development or post-registration (Pallardy and Bechara, 2017;Park et al, 2000;Uetrecht, 2013).…”

Section: Idiosyncratic and Hypersensitivity Reactionsmentioning

confidence: 99%

Optimizing drug discovery by Investigative Toxicology: Current and future trends

Beilmann¹

2018

ALTEX

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A report of t 4 -the transatlantic think tank for toxicology, a collaboration of the toxicologically oriented chairs in Baltimore, Konstanz and Utrecht sponsored by the Doerenkamp-Zbinden Foundation. The present report is the output of a three-day workshop sponsored by CAAT-Europe and Investigative Toxicology Leaders Forum (ITLF) held in Ranco (Italy) on July 10-12, 2017. The concepts and ideas presented here come from the individual participants and do not reflect the views and opinions of the organizations that they are representing. The debates were based on scientific discussions among the participants, without necessarily unanimous final agreement. § Members of the Investigative Toxicology Leaders Forum (ITLF)1 ICH Guideline M3 (R2). Non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals. CPMP/ICH/286/95. https://www.ema.europa.eu/documents/scientific-guideline/ich-m-3-r2-non-clinical-safety-studies-conduct-human-clinical-trials-marketing-authorization_en.pdf

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Section: Idiosyncratic and Hypersensitivity Reactionsmentioning

confidence: 99%

Optimizing drug discovery by Investigative Toxicology: Current and future trends

Beilmann¹

2018

ALTEX

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“…By contrast, the mechanisms underpinning emergence of mixed cholestatic-hepatitis are known less definitively. In numerous instances, evidence points to the relevance of idiosyncratic toxicity, typically associated with genetic variants controlling metabolite generation or immune response. , A generalized pathway for idiosyncratic immuno-allergic reaction, as depicted within Figure , would center first upon the formation by hepatic enzymes (commonly of the cytochrome P450 family) of reactive drug metabolites. An inability to adequately detoxify these species permits their adduction of cellular macromolecules, at which point they may function as haptens .…”

Section: Introductionmentioning

confidence: 99%

A Robust, Mechanistically Based In Silico Structural Profiler for Hepatic Cholestasis

Firman

Pestana

Rathman

et al. 2020

Chem. Res. Toxicol.

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Owing to the primary role which it holds within metabolism of xenobiotics, the liver stands at heightened risk of exposure to, and injury from, potentially hazardous substances. A principal manifestation of liver dysfunction is cholestasis -the impairment of physiological bile circulation from its point of origin within the organ to site of action at the small intestine. The capacity for early identification of compounds liable to exert cholestatic effect is of particular utility within the field of pharmaceutical development, where contribution towards candidate attrition is great. Shortcomings associated with present in vitro methodologies forecasting cholestasis render their predictivity questionable, permitting scope for adoption of computational toxicology techniques. As such, the intention of this study has been to construct an in silico profiler, founded upon clinical data, highlighting structural motifs most reliably associated with the endpoint. Drawing upon a list of greater than 1500 small molecular drugs, compiled and annotated by Kotsampasakou and Ecker, we have formulated a series of fifteen structural alerts. These describe fragments intrinsic within distinct pharmaceutical classes including psychoactive tricyclics, beta-lactam antimicrobials and oestrogenic/androgenic steroids. Description of the coverage and selectivity of each is provided, alongside consideration of underlying reactive mechanisms and relevant structure-activity concerns.Provision of mechanistic anchoring ensures that potential exists for framing within the adverse outcome pathway (AOP) paradigm -the chemistry conveyed through the alert in particular enabling rationalisation at the level of the molecular initiating event (MIE).

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“…Drug toxicity is commonly classified into two subtypes: Type A or intrinsic toxicity, which is dose dependent and related to the primary pharmacological target of the drug, and Type B or idiosyncratic toxicity (IT), which is unpredictable, occurs at frequencies of less than 1 in 5,000 cases ( 26 ), is not dose dependent, and is associated with off-target effects ( 27 ). Although decisions to withdraw a drug from the market can be made for a variety of reasons, unacceptable IT is believed to be the main reason ( 28 , 29 , 30 , 31 ). Given that IT is very rare, it can be unnoticeable in smaller test populations used for clinical trials and is often not detectable in animal models ( 27 ).…”

Section: Introductionmentioning

confidence: 99%

An integrative machine learning approach for prediction of toxicity-related drug safety

et al. 2018

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Role of the Adaptive Immune System in Idiosyncratic Drug-Induced Liver Injury

Cited by 5 publications

References 140 publications

Optimizing drug discovery by Investigative Toxicology: Current and future trends

Optimizing drug discovery by Investigative Toxicology: Current and future trends

A Robust, Mechanistically Based In Silico Structural Profiler for Hepatic Cholestasis

An integrative machine learning approach for prediction of toxicity-related drug safety

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