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.
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Document Type: Research Article
Publication date: 2009-11-01
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- Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:
In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.