oa Editorial: [Hot topic: Recent Advances in Drug Intolerance (Guest Editors: Jose A.G. Agundez)]

Drug intolerance constitutes an important cause of patient morbidity and mortality. Intolerance events can be detected at the final stages of drug development, during clinical trials or even after drug approval. Besides the risks derived from their clinical outcome, drug intolerance events may result in stopping drugs for further development, restriction of drug use or drug withdrawal from the market, in spite of the fact that many of the drugs causing intolerance are safe and efficient for most patients. For this reason, the identification of the mechanisms involved in drug intolerance and the early detection of at-risk individuals are key issues. Examples for severe drug intolerance events include among others hepatotoxicity, which ranges from sub-clinical elevations in liver enzyme concentrations to acute liver failure with a mean mortality of 10% for jaundiced patients with acute toxic hepatocellular damage [1]. Acute gastrointestinal bleeding is another common adverse effect, especially for non-steroidal antiinflammatory drugs, with a mortality rate between 7 and 11% [2]; and hypersensitivity reactions, including anaphylaxis, are also commonly caused by non-steroidal antiinflammatory drugs [3]. Besides licensed drugs, herbal and natural supplements are recognized as causing intolerance events with increasing frequency as patients turn more and more to alternative medicine [4]. The mechanisms underlying the interindividual variability in the susceptibility to drug intolerance are poorly understood. In recent years growing evidence points to a genetic basis for such susceptibility, either related to drug bioactivation or biodisposition, to variability in drug targets such as enzymes, transporters or receptors, as well as to genetic variability in general signaling and detoxication mechanisms [5-10]. Although studies are in progress, with few exceptions there is a paucity of published data on the relationship between genetic polymorphisms and drug intolerance. In addition, recent evidence suggests that pharmacogenomic studies are insufficient to predict adverse drug reactions [8] and that the combination of pharmacogenomic and metabolomics studies may be far more informative [11]. This special issue of Current Drug Metabolism on drug intolerance provides a collection of review articles covering basic and clinical topics related to drug intolerance, and identifies further aspects that should be investigated in detail. The paper by Andreu and coworkers discusses the potential role of metabolomics in drug intolerance. Hopefully the combination of metabolomics with pharmacogenomics will give essential information to identify at-risk subjects and to clarify the mechanisms related to bioactivation in drug intolerance. Two papers discuss major drug intolerance mechanisms. These include drug-induced liver injury in a review by Andrade and coworkers, and hypersensitivity reactions in a review by Cornejo and colleagues. These two review papers include clinical and diagnostic criteria as well as an update of causal mechanisms including genetic and non-genetic risk factors. Finally, two review papers exemplify aspects on drug intolerance. The paper by Van Asseldonk et al. discusses therapeutic drug monitoring, pharmacogenomics and drug intolerance of thiopurines, and the paper by Agundez and coworkers discusses basic and clinical aspects on the mechanisms involved in aspirin intolerance, including gastrointestinal complications and hypersensitivity. Further advances in drug intolerance research can be expected with the combined information obtained from proteomics, genomics, metabolomics, bioinformatics, immunology, toxicology and pharmacology. We hope that in the next few years the research effort dedicated to these studies will result in widely used tools capable of increasing the efficiency and safety of drug therapy, and/or to identify individuals with increased susceptibility to develop drug intolerance events. Hopefully, this information will also be useful to recover drugs that have been withdrawn from the market, for selective use in non-susceptible patients. I would like to thank, as Guest Editor of the special issue of Current Drug Metabolism, all the authors who kindly contributed to this issue and to our reviewers.