Metabolomics in drug intolerance

Adverse drug reactions appear during the clinical use of a drug and constitute a health problem, as they are an important cause of patient morbidity and mortality. In addition, they constitute a major drawback for drug development. Intolerance processes occurring after administration of low drug doses are known as idiosyncratic reactions or as hypersensitivity reactions; the most commonly accepted mechanism for immunological activation is the hapten hypothesis. Most drugs are not reactive per se towards proteins, hence in a number of cases bioactivation seems to be a prerequisite for adduct formation and the subsequent hypersensitivity reaction. Although biotransformation is normally associated with a decreased toxicity, metabolites are sometimes more toxic and reactive than the parent drug. Drug metabolizing enzymes develop their activities especially in liver, where reactive metabolites bind to proteins inducing hepatotoxicity, whereas in skin keratinocytes exhibit the highest biotransformation capability. In the present review, some specific examples of the toxicological consequences of drug biotransformation are given. They include nimesulide, metamizol, celecoxib, paracetamol, dapsone, sulfamethoxazole, amodiaquine, nevirapine, troglitazone, zileuton, felbamate, panadiplon, benzbromarone, fipexide and flutamide. In general, these examples are taken from the recent scientific literature, mostly published during the last decade.