Abstract
Idiosyncratic drug toxicity has led to the market withdrawal of many drugs in the past. Since animal experiments are not predictive of such toxicity, the pharmaceutical industry continues to seek new methodologies for the prevention of such effects. Although the mechanism of idiosyncratic drug toxicity remains unclear, immune reactions are likely involved. Although drugs with low molecular weights are typically not themselves immunogenic, these drugs may become haptens after being converted to chemically reactive metabolites and becoming covalently cross-linked to proteins. Therefore, screening tests to detect chemically reactive metabolites, most typically by trapping with glutathione, are carried out at early stages of drug development. More quantitative methods are used in later stages of drug development; radioassays for covalent binding (using 14Cor 3H-labeled compounds) are most frequently employed. A zone classification system created by combining previous assessment criteria for the chemically reactive metabolites in vitro (<50 pmole/mg-protein) and for the dose levels in vivo (<10 mg/day) could be used for risk assessment of drug candidates. A mechanism for idiosyncratic, drug-induced hepatotoxicity is proposed by analogy to virus-induced hepatitis, where cytotoxic T lymphocytes play an important role; we suggest that idiosyncrasy reflects the involvement of polymorphisms in the human leucocyte antigen-encoding loci. In fact, a strong correlation has been found between of idiosyncratic drug toxicity and specific human leucocyte antigen genotypes. Therefore, screening of patients for gene biomarkers is expected to reduce the clinical risk of idiosyncratic drug toxicity, thereby prolonging the life cycle of otherwise useful drugs.
Keywords: Adaptive immune reaction, chemically reactive metabolite, covalent protein binding, cytotoxic T lymphocytes, gene biomarker, go/no-go decision, human leucocyte antigen, idiosyncratic toxicity, innate immune reaction, intrinsic toxicity, judging criteria, risk assessment.
Current Medicinal Chemistry
Title:Idiosyncratic Drug Hepatotoxicity: Strategy for Prevention and Proposed Mechanism
Volume: 22 Issue: 4
Author(s): Toshihiko Ikeda
Affiliation:
Keywords: Adaptive immune reaction, chemically reactive metabolite, covalent protein binding, cytotoxic T lymphocytes, gene biomarker, go/no-go decision, human leucocyte antigen, idiosyncratic toxicity, innate immune reaction, intrinsic toxicity, judging criteria, risk assessment.
Abstract: Idiosyncratic drug toxicity has led to the market withdrawal of many drugs in the past. Since animal experiments are not predictive of such toxicity, the pharmaceutical industry continues to seek new methodologies for the prevention of such effects. Although the mechanism of idiosyncratic drug toxicity remains unclear, immune reactions are likely involved. Although drugs with low molecular weights are typically not themselves immunogenic, these drugs may become haptens after being converted to chemically reactive metabolites and becoming covalently cross-linked to proteins. Therefore, screening tests to detect chemically reactive metabolites, most typically by trapping with glutathione, are carried out at early stages of drug development. More quantitative methods are used in later stages of drug development; radioassays for covalent binding (using 14Cor 3H-labeled compounds) are most frequently employed. A zone classification system created by combining previous assessment criteria for the chemically reactive metabolites in vitro (<50 pmole/mg-protein) and for the dose levels in vivo (<10 mg/day) could be used for risk assessment of drug candidates. A mechanism for idiosyncratic, drug-induced hepatotoxicity is proposed by analogy to virus-induced hepatitis, where cytotoxic T lymphocytes play an important role; we suggest that idiosyncrasy reflects the involvement of polymorphisms in the human leucocyte antigen-encoding loci. In fact, a strong correlation has been found between of idiosyncratic drug toxicity and specific human leucocyte antigen genotypes. Therefore, screening of patients for gene biomarkers is expected to reduce the clinical risk of idiosyncratic drug toxicity, thereby prolonging the life cycle of otherwise useful drugs.
Export Options
About this article
Cite this article as:
Ikeda Toshihiko, Idiosyncratic Drug Hepatotoxicity: Strategy for Prevention and Proposed Mechanism, Current Medicinal Chemistry 2015; 22 (4) . https://dx.doi.org/10.2174/0929867321666140916122628
DOI https://dx.doi.org/10.2174/0929867321666140916122628 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Depression in Dementia or Dementia in Depression? Systematic Review of Studies and Hypotheses
Current Alzheimer Research From Leflunomide to Teriflunomide: Drug Development and Immunosuppressive Oral Drugs in the Treatment of Multiple Sclerosis
Current Neuropharmacology Novel Therapeutic Approaches in Pancreatic Cancer Based on Genomic Alterations
Current Pharmaceutical Design Implications of Epigenetic Mechanisms and their Targets in Cerebral Ischemia Models
Current Neuropharmacology New Chalcone Derivative: Synthesis, Characterization, Computational Studies and Antioxidant Activity
Letters in Organic Chemistry RNA Interference in Cancer: Targeting the Anti-Apoptotic Protein c-FLIP for Drug Discovery
Mini-Reviews in Medicinal Chemistry Randomised Trials of Graft Versus Host Disease Prophylaxis in Haemopoietic Stem Cell Transplantation
Reviews on Recent Clinical Trials Study in Treatment of Collagen-Induced Arthritis in DBA/1 Mice Model by Genistein
Current Pharmaceutical Design Plants Indicated by Brazilian Indians for Disturbances of the Central Nervous System: A Bibliographical Survey
Central Nervous System Agents in Medicinal Chemistry Medical Treatment of Peripheral Arterial Disease: Current Concepts and Future Options
Vascular Disease Prevention (Discontinued) An Overwiev of ORF Virus Infection in Humans and Animals
Recent Patents on Anti-Infective Drug Discovery subject Index To Volume 1
Current Drug Targets - Infectious Disorders Host-Pathogen Interactions and the Pathological Consequences of Acute Systemic Candida albicans Infections in Mice
Current Drug Targets Editorial [Hot Topic: Latest Developments in Pharmaceutical Design of Arachidonic Acid Metabolites: Prostaglandins, Thromboxanes, Hepoxilins and Isoprostanes (Executive Editors: J.-M. Dogne and K.-H. Ruan )]
Current Pharmaceutical Design Recent Advances in Drug Delivery: Potential and Limitations of Carbon Nanotubes
Recent Patents on Drug Delivery & Formulation Fish Oil Fatty Acids as Cardiovascular Drugs
Current Vascular Pharmacology Cytokines in the Pathogenesis of Chronic Obstructive Pulmonary Disease
Current Pharmaceutical Design Substance Abuse, HIV-1 and Hepatitis
Current HIV Research The Role of LRRK2 in Neurodegeneration of Parkinson Disease
Current Neuropharmacology Toll-Like Receptors in Sepsis: A Tale Still Being Told
Endocrine, Metabolic & Immune Disorders - Drug Targets