Elsevier

Toxicology

Volume 158, Issues 1–2, 2 February 2001, Pages 11-23
Toxicology

Metabolic activation in drug allergies

https://doi.org/10.1016/S0300-483X(00)00397-8Get rights and content

Abstract

Drug allergies are a major problem in the clinic and during drug development. At the present time, it is not possible to predict the potential of a new chemical entity to produce an allergic reaction (hypersensitivity) in patients in preclinical development. Such adverse reactions, because of their idiosyncratic nature, only become apparent once the drug has been licenced. Our present chemical understanding of drug hypersensitivity is based on the hapten hypothesis, in which covalent binding of the drug (metabolite) plays a central role in drug immunogenicity and antigenicity. If this theory is correct, then it should be possible to develop in vitro systems to assess the potential of drugs to bind to critical proteins, either directly or indirectly after metabolic activation to protein-reactive metabolites (bioactivation) and initiate hypersensitivity. The purpose of this review is to assess critically the evidence to support the hapten mechanism, and also to consider alternative mechanisms by which drugs cause idiosyncratic toxicity.

Introduction

Adverse drug reactions (ADRs) are a major complication of drug therapy (Pirmohamed et al., 1998, Lazarou et al., 1998). Such reactions are a significant cause of both patient morbidity and mortality. Most frustrating, from a pharmacological perspective, is that such reactions may preclude effective drug therapy, and if sufficiently serious, lead to drug withdrawal (Jefferys et al., 1998). Almost any body system may be adversely affected by drugs, but the most common serious reactions are those that involve the liver, skin, haemopoietic system, and more generalised toxicities such as systemic anaphylaxis. The immune system is thought to play a role in many of these ADRs. Many serious reactions show a high degree of individual (patient) selectivity. Indeed, it may be argued that it is almost impossible to develop drugs that are free of idiosyncratic toxicity, which can (in most cases) only be detected at the post-licensing stage of drug development.

There is therefore a need to develop test systems that predict the potential of new chemical entities to cause human toxicity. Implicit in this desire is the need to predict the type of toxicity to be tested for. A mechanistic framework is therefore required on which to develop hierarchical series of test systems for safety evaluation of a drug. We have classified ADRs according to the scheme in Table 1. Much progress has been made in making such reactions predictable, both at the preclinical and clinical stages of drug development. The one group of reactions that cannot yet be predicted during the preclinical, or early clinical phase of development, are type B reactions. Many of these reactions are referred to as hypersensitivity reactions because of their time-course and clinical presentation (Pirmohamed et al., 1998), but it is not always possible to prove an immunological mechanism.

Section snippets

The role of metabolism in drug toxicity

Drug metabolism has played an essential role in making ADRs more predictable and thus preventable (Fig. 1). In a chemical sense, an early success was the development of the Ames test for drug mutagenicity, which incorporates a mammalian drug-metabolising system, alongside a sensitive biological test system. More recently, high throughput screens for interactions with the individual cytochrome P450 enzymes, have enabled the drug metabolist to predict those new chemical entities that will show,

The role of drug metabolism in drug hypersensitivity

Our current understanding of hypersensitivity to low molecular weight compounds including drugs, is based on the hapten hypothesis (Fig. 2; Park et al., 1998, Uetrecht, 1999). It is immunological dogma that compounds of molecular weight of <1000 must be covalently bound to a high molecular weight (>50 000) proteins to be effective immunogens. Classical studies by Landsteiner (Landsteiner and Jacobs, 1935) showed that chemicals that bind covalently to protein are potent sensitising agents. Thus,

Blood dyscrasias

A notable feature of blood dyscrasias is the ability of drugs selectively to affect a particular formed element of blood in certain patients. What part does drug disposition and the immune response play in these ADRs?

Classical studies in patients and experimental animals showed that haemolytic anaemia induced by penicillin is a consequence of recognition of (drug) haptenated red cells by IgG or IgM antibodies and complement activation (Petz and Fundenberg, 1966, Levine and Redmond, 1967). The

Severe skin reactions

Skin reactions are relatively common and vary both in severity and the type of clinical presentation. For example, sulphonamides may induce both urticarial reactions (an IgE-mediated reaction) and toxic epidermal necrolysis (TEN), a T cell mediated reaction. TEN, which has a mortality rate of 30%, resembles graft-versus-host disease (Roujeau and Stern, 1994). The epidermis is infiltrated by activated T lymphocytes, the majority of which are CD8+ cells and macrophages, suggestive of a

Conclusions

There is convincing evidence that the formation of chemically reactive metabolites is an obligatory step in many types of drug toxicities. It is also clear that drugs and chemicals that react, in a covalent fashion, with proteins, either directly or indirectly via bioactivation, can induce an immune response. How this may then proceed to a hypersensitivity reaction, but only in certain individuals, remains uncertain. At present, it is only for penicillin that there is direct evidence for the

Acknowledgements

This work was supported by the Wellcome Trust, M.R.C. and the Sir Jules Thorn Charitable Trust.

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