Characterization of a Potential Animal Model of an Idiosyncratic Drug Reaction:  Nevirapine-Induced Skin Rash in the Rat

Shenton, Jacintha; Teranishi, Munehiro; Abu‐Asab, Mones; Yager, Julie A.; Uetrecht, Jack

doi:10.1021/tx034064+

Cited by 99 publications

(117 citation statements)

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“…The characteristics of NVP-induced skin rash in Brown Norway rats are very similar to the milder rashes that occur in humans, which suggests that the mechanisms are very similar. Specifically, in both humans and rats there is a 2-to 3-week delay between starting the drug and the onset of rash, and on re-exposure, symptoms are more severe and accelerated (Shenton et al, 2003;Taiwo, 2006). Females are more susceptible to developing rash than males in both Brown Norway rats and humans.…”

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confidence: 99%

A Study of the Specificity of Lymphocytes in Nevirapine-Induced Skin Rash

Chen

Tharmanathan²,

Mannargudi³

et al. 2009

J Pharmacol Exp Ther

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Nevirapine treatment can cause a skin rash. We developed an animal model of this rash and determined that the 12-hydroxylation metabolic pathway is responsible for the rash, and treatment of animals with 12-OH-nevirapine also leads to a rash. In the present study, we investigated the specificity of lymphocytes in nevirapine-induced skin rash. Brown Norway rats were treated with nevirapine or 12-OH-nevirapine to induce a rash. Lymph nodes were removed, and the response of lymphocytes to nevirapine and its metabolites/analogs was determined by cytokine production (enzyme-linked immunosorbent assay, enzyme-linked immunosorbent spot assay, and Luminex) and proliferation (alamar blue assay). Subsets of lymphocytes were depleted to determine which cells were responsible for cytokine production. Lymphocytes from animals rechallenged with nevirapine proliferated to nevirapine, but not to 12-OH-nevirapine or 4-chloro-nevirapine. They also produced interferon-␥ (IFN-␥) when exposed to nevirapine, significantly less when exposed to 4-chloro-nevirapine, and very little when exposed to 12-OHnevirapine, even though oxidation to 12-OH-nevirapine is required to induce the rash. Moreover, the specificity of lymphocytes from 12-OH-nevirapine-treated rats was the same, i.e., responding to nevirapine more than to 12-OH-nevirapine, even though these animals had never been exposed to nevirapine. A Luminex immunoassay showed that a variety of other cytokines/chemokines were also produced by nevirapine-stimulated lymphocytes. CD4 ϩ cells were the major source of IFN-␥. The specificity of lymphocytes in activation assays cannot be used to determine what initiated an immune response. This has significant implications for understanding the evolution of an immune response and the basis of the pharmacological interaction hypothesis.Nevirapine (NVP), marketed under the trade name Viramune (Boehringer Ingelheim GmbH, Ingelheim, Germany), is a non-nucleoside reverse transcriptase inhibitor used in the treatment of human immunodeficiency virus infections. Although effective, its use has been limited because of its propensity to cause skin rash and liver toxicity. In patients, skin rashes vary from mild erythematous, maculopapular rashes to more severe Stevens-Johnson syndrome or toxic epidermal necrolysis (Warren et al., 1998;Fagot et al., 2001). Our group discovered a novel animal model of NVPinduced skin rash in rats. The characteristics of NVP-induced skin rash in Brown Norway rats are very similar to the milder rashes that occur in humans, which suggests that the mechanisms are very similar. Specifically, in both humans and rats there is a 2-to 3-week delay between starting the drug and the onset of rash, and on re-exposure, symptoms are more severe and accelerated (Shenton et al., 2003;Taiwo, 2006). Females are more susceptible to developing rash than males in both Brown Norway rats and humans. Furthermore, the sensitivity to NVP-induced skin rash can be transferred with CD4 ϩ T cells from NVP-rechallenged rats to naive recipients ...

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confidence: 99%

A Study of the Specificity of Lymphocytes in Nevirapine-Induced Skin Rash

Chen

Tharmanathan²,

Mannargudi³

et al. 2009

J Pharmacol Exp Ther

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“…16 We discovered that nevirapine also causes a rash in rats. 17 The highest incidence (100%) occurred in female BN rats, but this appears to be largely due to kinetic factors. Male BN rats metabolize the drug much more rapidly than females and do not develop a rash at the same dose as females; however, if they are cotreated with aminobenzotriazole to inhibit cytochromes P450, males also develop a rash (J. Chen and J. Uetrecht, unpublished data, October 2003).…”

Section: Nevirapine-induced Skin Rash In the Ratmentioning

confidence: 98%

Role of animal models in the study of drug-induced hypersensitivity reactions

Uetrecht

2005

AAPS J

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A BSTRACTDrug-induced hypersensitivity reactions (DHRs) are a major problem, in large part because of their unpredictable nature. If we understood the mechanisms of these reactions better, they might be predictable. Their unpredictable nature also makes mechanistic studies very diffi cult, especially prospective clinical studies. Animal models are vital to most biomedical research, and they are almost the only way to test basic hypotheses of DHRs, such as the involvement of reactive metabolites. However, useful animal models of DHRs are rare because DHRs are also unpredictable in animals. For example, sulfonamide-induced DHRs in large-breed dogs appear to be valid because they are very similar to the DHRs that occur in humans; however, the incidence is only ~0.25%, and large-breed dogs are diffi cult to use as an animal model. Two more practical models are penicillamine-induced autoimmunity in the Brown Norway rat and nevirapine-induced skin rash in rats. The toxicity in these models is clearly immune mediated. In other models, such as amodiaquineinduced agranulocytosis/hepatotoxicity and halothaneinduced hepatotoxicity, the drug induces an immune response but there is no clinical toxicity. This fi nding suggests that regulatory mechanisms usually limit toxicity. Many of the basic characteristics of the penicillamine and nevirapine models, such as memory and tolerance, are quite different suggesting that the mechanisms are also signifi cantly different. More animal models are needed to study the range of mechanisms involved in DHRs; without them, progress in understanding such reactions is likely to be slow. K EYWORDS: animal models , hypersensitivity reactions , idiosyncratic drug reactions , penicillamine , nevirapine , popliteal lymph node assay INTRODUCTIONTo an immunologist, the term hypersensitivity implies an immune-mediated reaction. The term drug-induced hypersensitivity reaction (DHR) is used to describe a syndrome consisting of fever, rash, and involvement of various organs associated with drugs such as phenytoin, carbamazepine, abacavir, sulfonamides, and allopurinol; however, it is also frequently used to describe any idiosyncratic drug reaction. For many of the adverse reactions to be discussed in this review, it has not been conclusively demonstrated that they are immune mediated, and the term hypersensitivity reaction will be used broadly to refer to any idiosyncratic drug reaction that has features that suggest it is immune mediated. Another working hypothesis for this review, which is supported by a large amount of circumstantial evidence, 1 but in virtually no case proven, is that most DHRs are caused by reactive metabolites. Therefore, a major role of animal models is to test whether reactive metabolites are responsible for hypersensitivity reactions and further to determine how reactive metabolites provoke an immune response.A major characteristic of DHRs is their unpredictable or idiosyncratic nature. This means that at the present time it is impossible to predict which drug candidates will...

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“…In 2003, Shenton et al 80 described a rat model of nevirapineinduced tissue injury. Rats developed a mild-moderate skin rash following drug exposure.…”

Section: Animal Model Of Idiosyncratic Dilimentioning

confidence: 99%

Update on Advances in Research on Idiosyncratic Drug-Induced Liver Injury

Kim

Naisbitt

2016

Allergy Asthma Immunol Res

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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Drug-induced liver injury (DILI) is a major concern for public health, as well as for drug development in the pharmaceutical industry, since it can cause liver failure and lead to drug withdrawal from the market and black box warnings. Thus, it is important to identify biomarkers for early prediction to increase our understanding of mechanisms underlying DILI that will ultimately aid in the exploration of novel therapeutic strategies to prevent or manage DILI. DILI can be subdivided into 'intrinsic' and 'idiosyncratic' categories, although the validity of this classification remains controversial. Idiosyncratic DILI occurs in a minority of susceptible individuals with a prolonged latency, while intrinsic DILI results from drug-induced direct hepatotoxicity over the course of a few days. The rare occurrence of idiosyncratic DILI requires multicenter collaborative investigations and phenotype standardization. Recent progress in research on idiosyncratic DILI is based on key developments in 3 areas: (1) newly developed highthroughput genotyping across the whole genome allowing for the identification of genetic susceptibility markers, (2) new mechanistic concepts on the pathogenesis of DILI revealing a key role of drug-responsive T lymphocytes in the immunological response, and (3) broad multidisciplinary approaches using different platform "-omics" technologies that have identified novel biomarkers for the prediction of DILI. An association of a specific human leukocyte antigen (HLA) allele with DILI has been reported for several drugs. HLA-restricted T-cell immune responses have also been investigated using lymphocytes and T-cell clones isolated from patients. A microRNA, miR-122, has been discovered as a promising biomarker for the early prediction of DILI. In this review, we summarize recent advances in research on idiosyncratic DILI with an understanding of the key role of adaptive immune systems.

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Characterization of a Potential Animal Model of an Idiosyncratic Drug Reaction: Nevirapine-Induced Skin Rash in the Rat

Cited by 99 publications

References 27 publications

A Study of the Specificity of Lymphocytes in Nevirapine-Induced Skin Rash

A Study of the Specificity of Lymphocytes in Nevirapine-Induced Skin Rash

Role of animal models in the study of drug-induced hypersensitivity reactions

Update on Advances in Research on Idiosyncratic Drug-Induced Liver Injury

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