Jack Uetrecht

Idiosyncratic drug reactions: the reactive metabolite syndromes

Idiosyncratic drug reactions are unpredictable reactions that can result in significant morbidity and mortality. Severe reactions are often characterised by fever and internal organ involvement. Despite progress in the identification of reactive metabolites believed to be the cause of idiosyncratic reactions, the basic mechanisms remain elusive. Furthermore, because of the lack of consensus regarding definition of these syndromes, reporting, and therefore epidemiological data, are often unreliable. Research is needed to explore further the pathophysiology of these reactions, so that better diagnostic tests and treatment methods can be developed.

Mechanisms of Immune-Mediated Liver Injury

Hepatic inflammation is a common finding during a variety of liver diseases including drug-induced liver toxicity. The inflammatory phenotype can be attributed to the innate immune response generated by Kupffer cells, monocytes, neutrophils, and lymphocytes. The adaptive immune system is also influenced by the innate immune response leading to liver damage. This review summarizes recent advances in specific mechanisms of immune-mediated hepatotoxicity and its application to drug-induced liver injury. Basic mechanisms of activation of lymphocytes, macrophages, and neutrophils and their unique mechanisms of recruitment into the liver vasculature are discussed. In particular, the role of adhesion molecules and various inflammatory mediators in this process are explored. In addition, the authors describe mechanisms of liver cell damage by these inflammatory cells and critically evaluate the functional significance of each cell type for predictive and idiosyncratic drug-induced liver injury. It is expected that continued advances in our understanding of immune mechanisms of liver injury will lead to an earlier detection of the hepatotoxic potential of drugs under development and to an earlier identification of susceptible individuals at risk for predictive and idiosyncratic drug toxicities.

The role of leukocyte-generated reactive metabolites in the pathogenesis of idiosyncratic drug reactions

Evidence strongly suggests that many adverse drug reactions, including idiosyncratic drug reactions, involve reactive metabolites. Furthermore, certain functional groups, which are readily oxidized to reactive metabolites, are associated with a high incidence of adverse reactions. Most drugs can probably form reactive metabolites, but a simple comparison of covalent binding in vitro is unlikely to provide an accurate indication of the relative risk of a drug causing an idiosyncratic reaction because it does not provide an indication of how efficiently the metabolite is detoxified in vivo. In addition, the incidence and nature of adverse reactions associated with a given drug is probably determined in large measure by the location of reactive metabolite formation, as well as the chemical reactivity of the reactive metabolite. Such factors will determine which macromolecules the metabolites will bind to, and it is known that covalent binding to some proteins, such as those in the leukocyte membrane, is much more likely to lead to an immune-mediated reaction or other type of toxicity. Some reactive metabolites, such as acyl glucuronides, circulate freely and could lead to adverse reactions in almost any organ; however, most reactive metabolites have a short biological half-life, and although small amounts may escape the organ where they are formed, these metabolites are unlikely to reach sufficient concentrations to cause toxicity in other organs. Many idiosyncratic drug reactions involve leukocytes, especially agranulocytosis and drug-induced lupus. We and others have demonstrated that drugs can be metabolized by activated neutrophils and monocytes to reactive metabolites. The major reaction appears to be reaction with leukocyte-generated hypochlorous acid. Hypochlorous acid is quite reactive, and therefore it is likely that many other drugs will be found that are metabolized by activated leukocytes. Some neutrophil precursors contain myeloperoxidase and the NADPH oxidase system, and it is likely that these cells can also oxidize drugs. Therefore, although there is no direct evidence, it is reasonable to speculate that reactive metabolites generated by activated leukocytes, or neutrophil precursors in the bone marrow, could be responsible for drug-induced agranulocytosis and aplastic anemia. This could involve direct toxicity or an immune-mediated reaction. These mechanisms are not mutually exclusive, and it may be that both mechanisms contribute to the toxicity, even in the same patient. In the case of drug-induced lupus, a prevalent hypothesis for lupus involves modification of class II MHC antigens.(ABSTRACT TRUNCATED AT 400 WORDS)

Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert's syndrome

Gilberts syndrome occurs in 5%-7% of the human population and is caused by an inherited deficiency in the glucuronidation of endogenous bilirubin, resulting in its accumulation and jaundice. The authors of the present study have previously shown that rats with a similar deficiency in bilirubin glucuronidation (Gunn rats) had reduced glucuronidation and enhanced susceptibility to the toxicity of the widely used analgesic, acetaminophen. Acetaminophen is eliminated primarily by glucuronidation, which prevents its cytochrome P-450-catalysed bioactivation to a hepatotoxic reactive intermediate. The purpose of this study was to determine whether people with Gilberts syndrome had reduced glucuronidation and enhanced bioactivation of acetaminophen. Therefore, the biotransformation of acetaminophen, 20 mg/kg IV, was investigated in six subjects with Gilberts syndrome (total bilirubin, 41 +/- 6 mumol/L; mean +/- SE) and six normal controls (total bilirubin, 11 +/- 2 mumol/L; P less than 0.01). Formation of the acetaminophen glucuronide conjugate measured by high-performance liquid chromatography was quantified by the ratio of the area under the plasma concentration-time curve (AUC) from 0 to 2 hours for the acetaminophen glucuronide divided by the AUC for acetaminophen. Acetaminophen bioactivation was quantified by the molar percentage of acetaminophen excreted in the urine during 24 hours as glutathione-derived conjugates (cysteine and mercapturic acid). Acetaminophen glucuronide formation in subjects with Gilberts syndrome was 31% lower than that in normal controls (0.27 +/- 0.05 vs. 0.39 +/- 0.03; P less than 0.05), and bioactivation was 1.7-fold higher (3.5% +/- 0.4% vs. 2.1% +/- 0.3%; P less than 0.05). One control subject with normal bilirubin glucuronidation had substantially decreased acetaminophen glucuronide formation (0.20) and enhanced bioactivation (4.8%). Among all subjects, glucuronidation correlated inversely with bioactivation (r = -0.84; P less than 0.001), indicating that a decrease in a major pathway of elimination can shunt more drug through the toxifying route. Thus, a deficiency in bilirubin UDP-glucuronosyltransferase, evidenced by jaundice, can be paralleled by a deficiency in glucuronidation of other compounds. In these cases, jaundice can be a phenotypic determinant of enhanced acetaminophen bioactivation. On the other hand, some people with normal bilirubin glucuronidation may have a deficiency in the glucuronidation of acetaminophen; these people are not easily recognized.(ABSTRACT TRUNCATED AT 400 WORDS)

Idiosyncratic Adverse Drug Reactions: Current Concepts

Idiosyncratic drug reactions are a significant cause of morbidity and mortality for patients; they also markedly increase the uncertainty of drug development. The major targets are skin, liver, and bone marrow. Clinical characteristics suggest that IDRs are immune mediated, and there is substantive evidence that most, but not all, IDRs are caused by chemically reactive species. However, rigorous mechanistic studies are very difficult to perform, especially in the absence of valid animal models. Models to explain how drugs or reactive metabolites interact with the MHC/T-cell receptor complex include the hapten and P-I models, and most recently it was found that abacavir can interact reversibly with MHC to alter the endogenous peptides that are presented to T cells. The discovery of HLA molecules as important risk factors for some IDRs has also significantly contributed to our understanding of these adverse reactions, but it is not yet clear what fraction of IDRs have a strong HLA dependence. In addition, with the exception of abacavir, most patients who have the HLA that confers a higher IDR risk with a specific drug will not have an IDR when treated with that drug. Interindividual differences in T-cell receptors and other factors also presumably play a role in determining which patients will have an IDR. The immune response represents a delicate balance, and immune tolerance may be the dominant response to a drug that can cause IDRs.

A fresh look at the mechanism of isoniazid-induced hepatotoxicity.

Isoniazid (INH)‐induced hepatotoxicity remains a significant clinical problem, and the current mechanistic hypothesis is incomplete; it is simply referred to as metabolic idiosyncrasy, 1 which is believed to involve cytotoxicity caused by bioactivation of acetylhydrazine, 2 a metabolite of INH. However, this hypothesis is based on animal studies, involving characteristics that are very different from those that pertain to hepatotoxicity in humans, such as delayed onset. This issue therefore deserves a fresh look.

Screening for the potential of a drug candidate to cause idiosyncratic drug reactions

Toxicity testing has been ineffective in the prediction of drug candidates that will be associated with a relatively high incidence of idiosyncratic drug reactions (IDRs). Circumstantial evidence suggests the involvement of reactive metabolites in the aetiology of these reactions and this has prompted several companies to screen drug candidates for the formation of such compounds. Most drugs form at least one reactive metabolite. To develop efficient prediction methods, a better understanding of the basic mechanisms involved is essential. This review highlights the current mechanistic hypotheses of IDRs and discusses future directions in the development of better predictive tests.

Drug-induced hypothyroidism : the thyroid as a target organ in hypersensitivity reactions to anticonvulsants and sulfonamides

Inherited defects in detoxification of reactive metabolites of drugs predispose patients to “hypersensitivity” reactions. Covalent interaction of metabolites with cell macromolecules leads to cytotoxic and immunologic outcomes, manifested clinically by multisystem syndromes with variable organ involvement. Hypothyroidism developed in 5 of 202 patients (age range, 1 to 81 years) we investigated for hypersensitivity reactions to anticonvulsants or sulfonamides shortly after their reaction. None had previous personal or family histories of autoimmune disease. All had low thyroxine levels, elevated levels of thyroid stimulating hormone, and autoantibodies including antimicrosomal antibodies. Patients were 2 to 18 years of age at presentation, and two were male. All returned to a euthyroid state within a year of presentation, and all remain well. The demographics, clinical presentation, and course of the patients is atypical of idiopathic lymphocytic thyroiditis. We investigated the pathogenesis of thyroid toxicity using the hydroxylamine metaboUte of sulfamethoxazole as a model. The hydroxyalmine was toxic to thyroid cells in vitro, which did or did not express thyroid peroxidase activity, whereas the parent sulfonamide was toxic only to cells with active thyroid peroxidase. The purified enzyme converted sulfamethoxazole to the hydroxylamine. Formation of reactive drug metabolites by thyroid peroxidase in a host who is genetically unable to detoxify the metabolites may lead directly to cytotoxicity. Covalent binding to macromolecules, including thyroid peroxidase, also may lead to expression of neoantigens and formation of autoantibodies. Patients who have sustained hypersensitivity reactions to drugs should be investigated for possible involvement of the thyroid.

The danger hypothesis applied to idiosyncratic drug reactions.

PURPOSE OF REVIEW Idiosyncratic drug reactions pose a significant clinical threat and hamper drug development. The idiosyncratic nature of these reactions has made mechanistic studies exceedingly difficult, and yet without a better understanding of the mechanisms involved it is unlikely that much progress can be made in dealing with the problem. Several working hypotheses have been used to study these reactions, but none fits all of the characteristics that are observed. Borrowed from immunology, the danger hypothesis has most recently been used to explain several characteristics of these reactions. The present review describes the danger hypothesis and compares it with previous hypotheses to determine how well each fits with the observed characteristics of the reactions. RECENT FINDINGS Slow progress in the field continues and it is important to use new observations, such as identifying T cells that recognize drugs in the absence of reactive metabolite formation, to test and refine the working hypotheses. However, the development of animal models of idiosyncratic drug reactions as well as progress in basic immunology and genomics are likely to accelerate progress in this area in the near future. SUMMARY No one model fits the characteristics of all idiosyncratic drug reactions; however, the danger model provides a new perspective and suggests avenues of research that have the potential to increase our ability to predict and prevent such reactions significantly.

Immune-Mediated Adverse Drug Reactions

Many adverse drug reactions are mediated by the immune system. This can be because the therapeutic effect of the drug targets the immune system. For example, immunosuppressive drugs increase the risk of infections. It is paradoxical that some immunosuppressive drugs can lead to autoimmune reactions. Another mechanism by which drugs can cause an adverse reaction involves an idiosyncratic response to the drug such as an immune-mediated skin rash. These idiosyncratic drug reactions (IDRs) are difficult to study because of the paucity of valid animal models and their unpredictable nature. Therefore, much of our mechanistic knowledge of IDRs is based on inferences from the clinical characteristics of IDRs rather than on controlled mechanistic studies. In general, IDRs are associated with a delay between starting the drug and the onset of the adverse reaction, and the typical delay is different for different types of IDRs. In contrast, on rechallenge, there is usually a rapid onset of the adverse reaction, which is characteristic of an amnestic immune response. The absence of such a rapid response is usually considered evidence that an IDR is not immune-mediated; yet, there are immune-mediated IDRs that do not have an amnestic response. One possible reason for the lack of an amnestic response is if the IDR has a strong autoimmune component leading to deletion of autoimmune memory cells when the drug is withdrawn. Another interesting characteristic of IDRs is that there are many drugs that can cause different types of IDRs in different patients. A possible explanation is that although the immune response is induced by a drug, it is directed against an autoantigen, and interindividual differences in the immune repertoire determine which autoantigen and target organ are affected. Although testing these hypotheses represents a difficult challenge, the importance of these adverse reactions makes it a high priority.