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

doi:10.1016/S1359-6446(03)02816-2

Drug Discovery Today

Volume 8, Issue 18, 15 September 2003, Pages 832-837

https://doi.org/10.1016/S1359-6446(03)02816-2 Get rights and content

Abstract

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.

Section snippets

The problem of IDRs

Some of the adverse reactions responsible for withdrawals are a result of drug interactions or known pharmacological properties, such as prolongation of the cardiac QT interval; such adverse reactions are more easily predicted today than in the past [2]. More problematic are the truly idiosyncratic reactions that do not involve the known pharmacological properties of the drug. Such reactions have characteristics suggesting that they are immune-mediated: there is a delay of a week or more before

Hapten hypothesis

The general characteristics of most IDRs suggest that they are mediated by the immune system. If this is the case, the idiosyncratic nature of these reactions is easier to rationalize because some people are allergic to particular compounds, whereas others are not. There are some examples, such as allergic reactions to penicillin and halothane hepatitis, in which clear involvement of the immune system has been demonstrated; however, in most cases, involvement of the immune system is only

Quinones and related structures

There are many different types of reactive metabolites that can be formed by drugs, a detailed description of which can be found elsewhere [19]. In general, reactive metabolites are either electrophiles (i.e. electron deficient) or free radicals. Electrophiles usually react with biological nucleophiles, such as glutathione or nucleophilic groups on proteins, such as sulfhydryl or amino groups. A common type of reactive metabolite are quinine compounds and related quinone imines and quinone

Avoiding suspect functional groups

The first step in avoiding reactive metabolites is to avoid, whenever possible, functional groups, such as aryl amines, that are known to readily form reactive metabolites [21]. In addition, metabolic pathways of the drug that would be expected to form reactive metabolites can often be anticipated. Early metabolic screens might produce metabolites that point to the formation of reactive intermediates. An obvious example of this is the finding of a glutathione conjugate, which is usually formed

Future directions

The development of better screening tests to predict IDR potential would clearly have a major impact on drug development (potential screening methods are listed in Box 1). However, a fundamental question remains: what is the role of reactive metabolites? Various other screens have been proposed to answer this question and are currently being used although they lack validation – many involve simple in vitro cytotoxicity assays – but results thus far are not encouraging. High concentrations are

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Idiosyncratic reactions are one of the major causes of drug treatment limitations or market withdrawals, and likely involve the formation of reactive metabolites. Because of their unstable nature, reactive species are usually discovered as stable conjugates by glutathione (GSH) trapping rather than by direct detection. The GSH conjugates are then detected by neutral loss scanning of 129 Da or precursor ion scanning at m/z 272, but the conjugation sites can only be identified by comparison with reference standards. In the present study, the fragmentation behaviors of 52 GSH conjugates belonging to five structural classes (aliphatic, aromatic, benzylic, disulfide, and thioester) were investigated in both positive and negative electrospray ionization modes by high-resolution mass spectrometry with suitable collision energies such that the relative abundance of the parent ion was approximately 50% of the most abundant product ion. Several structural-diagnostic fragmentations were identified: aliphatic conjugates gave i/j-type ions upon cleavage of the CS bond between the drug and GSH, and d/k-type ions formed by the cleavage of the cysteinyl CS bond, with approximately equal intensity, in both positive and negative modes, whereas aromatic conjugates only possessed d/k-type ions, and benzylic conjugates primarily yielded i/j-type ions. Disulfide conjugates typically produced dehydrogenated GS⁻ fragment ions ([i-2H]-type) in negative mode, and thioester conjugates displayed sequential losses of pyroglutamic acid and water ([e-H₂O]-type) in positive mode. A fragmentation-based method was thus established to facilitate the discrimination of these five classes of GSH conjugates, thereby providing insight into the bioactivation mechanisms and supporting lead optimization.
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Citation Excerpt :
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ReviewScreening for the potential of a drug candidate to cause idiosyncratic drug reactions

Abstract

Section snippets

The problem of IDRs

Hapten hypothesis

Quinones and related structures

Avoiding suspect functional groups

Future directions

Chem. Biol. Interact.

Toxicol. Appl. Pharmacol.

Immunol. Today

Semin. Immunol.

Semin. Immunol.

Toxicology

J. Invest. Dermatol.

Lancet

Timing of new Black Box Warnings and withdrawals for prescription medications

J. Am. Med. Assoc.

Drugs that prolong QT interval as an unwanted effect: assessing their likelihood of inducing hazardous cardiac dysrhythmias

Expert Opin. Pharmacother.

Immunological principles of adverse drug reactions: the initiation and propagation of immune responses elicited by drug treatment

Drug Saf.

Hepatotoxicity with thiazolidinediones: is it a class effect?

Drug Saf.

Safety review of adult clinical trial experience with lamotrigine

Drug Saf.

The immunologic and metabolic basis of drug hypersensitivities

Annu. Rev. Pharmacol.

Role of drug disposition in drug hypersensitivity: a chemical, molecular, and clinical perspective

Chem. Res. Toxicol.

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