The Role of Reactive Drug Metabolites in Immune-Mediated Adverse Drug Reactions

1997 ◽  
Vol 31 (11) ◽  
pp. 1378-1387 ◽  
Author(s):  
David A Hess ◽  
Michael J Rieder
Keyword(s):  
Immune Response ◽  
Drug Therapy ◽  
Adverse Drug Reactions ◽  
Covalent Binding ◽  
Cellular Damage ◽  
Hypersensitivity Reactions ◽  
Drug Reactions ◽  
Drug Metabolites ◽  
Immune Mediated

OBJECTIVE: To highlight recent advances in the understanding of adverse drug reactions (ADRs), with a focus on models outlining interactions between drug metabolism, disease processes, and immunity. Specific mechanisms that identify the metabolic pathways responsible for drug bioactivation to reactive drug metabolites (RDMs) involved in the initiation and propagation of specific immune-mediated hypersensitivity reactions are discussed. Drug classes well known to be associated with immune-mediated ADRs are reviewed and the clinical implications of current research are discussed. DATA SOURCES: Original experimental research and immunologic review articles relevant to ADR diagnosis and etiology. DATA EXTRACTION: Results of relevant in vitro experiments and clinical reactions to drug therapy were compiled and reviewed. Critical discoveries concerning the identification of RDMs involved in ADRs were highlighted, with respect to RDM involvement in the production of an immune response to drug haptens. DATA SYNTHESIS: Drug adverse effects are classified according to clinical characteristics, immune interactions, and mechanistic similarities. Cytochrome P450 bioactivation of drug molecules to RDMs is a prerequisite to many ADRs. An electrophilic metabolite may react with cellular macromolecules (i.e., lipids, proteins, nucleic acids), resulting in direct cellular damage and organ toxicity. Covalent binding of an RDM to cellular macromolecules may also result in the formation of a hapten that is capable of eliciting a cellular or humoral immune response against drug or protein epitopes, culminating in the characteristic symptoms of hypersensitivity reactions. Mechanistic details concerning the identification of stable protein-metabolite conjugates and their interaction with the immune system remain unclear. Genetic imbalance between bioactivation and detoxification pathways, as well as reduced cellular defense against RDMs due to disease or concomitant drug therapy, act as risk factors to the onset and severity of ADRs. CONCLUSIONS: Adverse reactions to drug therapy cause significant morbidity and mortality. Identification of the pathways involved in drug bioactivation and detoxification may elucidate the potential of chemical agents to induce immune-mediated ADRs. Understanding the mechanisms of ADRs to current xenobiotics is helpful in the prevention and management of ADRs, and may prove useful in the design of novel therapeutic agents with reduced incidence of severe adverse events.

An update on HLA alleles associated with adverse drug reactions

2017 ◽  
Vol 32 (2) ◽  
Author(s):  
Ingrid Fricke-Galindo ◽  
Adrián LLerena ◽  
Marisol López-López
Keyword(s):  
Adverse Drug Reactions ◽  
Morbidity And Mortality ◽  
Hypersensitivity Reactions ◽  
Drug Reactions ◽  
Hla Alleles ◽  
Immune Mediated

AbstractAdverse drug reactions (ADRs) are considered as an important cause of morbidity and mortality. The hypersensitivity reactions are immune-mediated ADRs, which are dose-independent, unpredictable and have been associated with several

Clinical Phenotypes of Severe Cutaneous Drug Hypersensitivity Reactions

2019 ◽  
Vol 25 (36) ◽  
pp. 3840-3854 ◽  
Author(s):  
Hakan Guvenir ◽  
Tugba Arikoglu ◽  
Emine Vezir ◽  
Emine Dibek Misirlioglu
Keyword(s):  
Adverse Drug Reactions ◽  
Drug Hypersensitivity ◽  
Stevens Johnson Syndrome ◽  
Facial Oedema ◽  
Hypersensitivity Reactions ◽  
Drug Reactions ◽  
Cutaneous Manifestations ◽  
Clinical Phenotypes ◽  
Drug Eruptions ◽  
Drug Hypersensitivity Reactions

Drug hypersensitivity reactions are clinically heterogenous ranging from mild to severe. Most drug hypersensitivity reactions are accompanied by cutaneous manifestations. Fever, mucous membrane involvement, large blisters, facial oedema, pustulosis and visceral involvement are clinical features that lead to suspicion of severe adverse drug reactions. Severe cutaneous adverse drug reactions (SCARs) include Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis. Serum sickness like reactions, drug induced vasculitis and generalized bullous fixed drug eruptions are less severe clinical entities. SCARs are uncommon but associated with significant morbidity and mortality. Physician should be aware of specific red flags and danger signs to immediately identify these reactions. Immediate drug withdrawal is mandatory. Early diagnosis and appropriate treatment significantly affect the prognosis of the disease. The purpose of our review is to discuss clinical phenotypes of severe cutaneous drug hypersensitivity reactions.

scholarly journals Investigating the Mechanism of Trimethoprim-Induced Skin Rash and Liver Injury

2021 ◽  
Author(s):  
Yanshan Cao ◽  
Ahsan Bairam ◽  
Alison Jee ◽  
Ming Liu ◽  
Jack Uetrecht
Keyword(s):  
Liver Injury ◽  
Skin Rash ◽  
Covalent Binding ◽  
Reactive Metabolites ◽  
Important Data ◽  
Drug Induced ◽  
Interindividual Differences ◽  
Immune Mediated ◽  
Sulfate Conjugate

Abstract Trimethoprim (TMP)-induced skin rash and liver injury are likely to involve the formation of reactive metabolites. Analogous to nevirapine-induced skin rash, one possible reactive metabolite is the sulfate conjugate of α-hydroxyTMP, a metabolite of TMP. We synthesized this sulfate and found that it reacts with proteins in vitro. We produced a TMP-antiserum and found covalent binding of TMP in the liver of TMP-treated rats. However, we found that α-hydroxyTMP is not a substrate for human sulfotransferases, and we did not detect covalent binding in the skin of TMP-treated rats. Although less reactive than the sulfate, α-hydroxyTMP was found to covalently bind to liver and skin proteins in vitro. Even though there was covalent binding to liver proteins, TMP did not cause liver injury in rats or in our impaired immune tolerance mouse model that has been able to unmask the ability of other drugs to cause immune-mediated liver injury. This is likely because there was much less covalent binding of TMP in the livers of TMP-treated mice than TMP-treated rats. It is possible that some patients have a sulfotransferase that can produce the reactive benzylic sulfate; however, α-hydroxyTMP, itself, has sufficient reactivity to covalently bind to proteins in the skin and may be responsible for TMP-induced skin rash. Interspecies and interindividual differences in TMP metabolism may be one factor that determines the risk of TMP-induced skin rash. This study provides important data required to understand the mechanism of TMP-induced skin rash and drug-induced skin rash in general.

Drug Allergy

2012 ◽  
Vol 5 (6) ◽  
pp. 319-324
Author(s):  
Helen E. Smith
Keyword(s):  
Adverse Drug Reactions ◽  
Drug Allergy ◽  
Therapeutic Drug ◽  
Drug Reactions ◽  
Immune Mediated ◽  
Allergy Drug ◽  
The Way

Adverse drug reactions are a major cause of morbidity, complicating over 5% of therapeutic drug courses. The majority of these events are due to common predictable mechanisms linked to the way the drug works, but about 5% of all reactions are immune-mediated and constitute true allergy. Drug allergy is one of the potential causes of anaphylaxis, angioedema and urticaria and should always be considered when a patient presents with one of these conditions.

Distribution of drug-metabolizing enzymes coding genes CYP2D6, CYP3A4, CYP3A5 alleles in a group of healthy Turkish population

2018 ◽  
Vol 44 (2) ◽  
pp. 142-146
Author(s):  
İsmail Ün ◽  
İ. Ömer Barlas ◽  
Nisa Uyar ◽  
Bahar Taşdelen ◽  
Naci Tiftik
Keyword(s):  
Drug Therapy ◽  
Adverse Drug Reactions ◽  
Low Frequency ◽  
Turkish Population ◽  
Allele Frequencies ◽  
Drug Reactions ◽  
Metabolizing Enzymes ◽  
Frequency Distributions ◽  
Allelic Frequencies ◽  
Hardy Weinberg Equilibrium

Abstract Objective: Variant alleles in specific ethnic groups are important for personalized drug therapy regimens and adverse drug reactions. Therefore, the aim of this study was to investigate allelic frequencies of the CYP2D6*1, CYP3A4*5, CYP3A4*18, CYP3A5*2 and CYP3A5*4 in a group of Turkish population. Materials and methods: Three hundred and six unrelated healthy subjects who were accepted as blood donors to the Mersin University Blood Bank were included in the study after informed consent. Allelic frequencies of the CYP2D6*1 (rs3892097), CYP3A4*5 (rs55901263), CYP3A4*18 (rs28371759), CYP3A5*2 (rs28365083) and CYP3A5*4 (rs56411402) were determined by using polymerase chain reaction-restriction fragment length polymorphism assays. Results: CYP2D6 allele frequencies in detected group was 100% for CYP2D6*1 (WT/WT). CYP3A4 allele frequencies of subjects were 100% for CYP3A4*5 (C/C) and CYP3A4*18 (T/T). CYP3A5 allele were in Hardy-Weinberg equilibrium for CYP3A5*2 (p=0.142) and frequencies for C and A allele were 91% and 9% respectively. CYP3A5 allele frequencies of subjects was 100% for CYP3A5*4 (WT/WT). Conclusion: Screening of low frequency alleles by pharmacogenetic testing must not be omitted to optimize pharmacotherapy and avoid severe drug toxicities. Frequency distributions of the identified polymorphisms in the present study may contribute to the personalized drug therapy regimens and prediction of possible adverse drug reactions in the Turkish population.

scholarly journals Drug-Drug-Dietary interactions in pharmacotherapy of GIT medication: A review

2020 ◽  
Vol 11 (SPL4) ◽  
pp. 2903-2909
Author(s):  
Akula sowjanya ◽  
Abhisek Pal
Keyword(s):  
Drug Therapy ◽  
Drug Interactions ◽  
Food Consumption ◽  
Adverse Drug Reactions ◽  
Drug Effect ◽  
Google Scholar ◽  
Drug Reactions ◽  
Common Drug ◽  
Different Types ◽  
Dietary Interactions

Successful drug therapy depends on the interaction between drug-drug and drug-diet. Drug interactions are a vital reason for causing adverse drug reactions and modify one drug effect by another drug and these kinds of interactions can increase or decrease the effectiveness of the drug. Polypharmacy could be a major risk for Drug-Drug and Drug-food interactions. Food Consumption can alter the effect of drugs by interfering either with their pharmacokinetics or pharmacodynamics processes. Anti-ulcer drugs are used to treat different types of ulcer and that may interact with another drug showing undesirable effects. GIT medications interfere with another type of medication either with at the pharmacokinetic and pharmacodynamic level. The main objective of this article is to review data regarding common Drug-drug & Drug-food interactions related to GIT medications. Data was collected from Google Scholar, PubMed, and Scopus databases, and they were reviewed for publication on drug-drug & drug-food interactions related to GIT medications. This data is very helpful for pharmacists while reviewing and analyzing prescribed medication, especially in geriatrics prescriptions.

Sign in / Sign up

Export Citation Format

Share Document