From toxic precursors to safe drugs. Mechanisms and relevance of idiosyncratic drug reactions.

In adverse drug reactions, effects accounted for by the pharmacological profile of the drug may be distinguished from sometimes bizarre, unpredictable events ("idiosyncrasies"). In the majority of cases, the latter are due to reactive intermediates formed by members of the cytochrome P450 family of enzymes. These products are usually formed at very low quantities. However, genetic disposition (e.g. by enhanced expression of the catalyzing enzyme or failure of protective factors such as glutathione) or certain external conditions (for example comedication of inducers of drug metabolism) may lead to toxic intermediates being available at relevant quantities. Once generated, these metabolites will react with macromolecules and finally cause cell necrosis. Necrosis may result from direct damage to functions essential to the cell or be secondary to harmful immune reactions activated by recognition of the new structures as neoantigens. As the principal site of drug metabolism, the liver is most frequently affected by idiosyncratic reactions, which often enough are recognized only after large numbers of patients have been treated. The idiosyncratic potential of a drug relates to its chemical structure rather than its pharmacological mechanism. Risks are evident if biotransformation yields products with chemical substructures such as quinones, phenoles, acyl halides, aromatic and hydroxyl amines. There are numerous cases of precursor drugs with idiosyncratic potential that have been replaced or marginalized by agents with more favorable chemical properties. Examples include beta 1-preferential beta-adrenoceptor antagonists (toxic precursor: practolol) and the choline esterase inhibitors used in treatment of Alzheimer's disease. In the latter group, tacrine (CAS 321-64-2) gives rise to high liver enzyme levels in about 30% of the patients, an effect not shared with more recent, chemically different entities. A similar case can be made for the insulin sensitizer troglitazone (CAS 97322-87-7) (marketed, now withdrawn in the USA) and its successors rosiglitazone (CAS 122320-73-4) and pioglitazone (CAS 111025-46-8). Due to its different chemical structure, only troglitazone can be transformed into a reactive quinone metabolite, a process that may be accelerated by the drug inducing its own metabolism. In agreement with this view, there is no evidence of specific hepatic toxicity with the two successor drugs. Ongoing progress in molecular toxicology may aid in minimizing idiosyncratic hazards already at early stages of drug development.