Deleterious Effects of Reactive Metabolites 外文参考文献.docVIP

review Oxidative Medicine and CellularLongevity 3:4, 238-253; July/August 2010; ? 2010 Landes Bioscience Deleterious e?ects of reactive metabolites Sabry M. Attia Department of Pharmacology and Toxicology; College of Pharmacy; King Saud University; riyadh, Saudi Arabia Key words: metabolism, reactive metabolites, adverse drug reactions, drug design Type B adverse drug reactions can affect any organ, but the most common organs involved are liver, skin, and bone mar- row. The life-threatening type B adverse drug reactions noted A number of drugs have been withdrawn from the market or severely restricted in their use because of unexpected toxicities that become apparent only after the launch of new drug entities. Circumstantial evidence suggests that, in most cases, reactive metabolites are responsible forthese unexpected toxicities. in this review, a general overviewof the types of reactive metabolites and the consequences of their formation are presented. The current approaches to evaluate bioactivation potential of new compounds with particular emphasis on the advantages and limitation of these procedures will be discussed. reasonable reasons forthe excellent safety record of certain drugs susceptible to bioactivation will also be explored and should provide valuable guidance in the use of reactive-metabolite assessments when nominating drug candidates fordevelopment. This will, in turn, help us to design and bring saferdrugs to the market. for drugs include hepatotoxicity, severe cutaneous reactions, 3-5 aplastic anaemia and blood dyscrasias. Amongst these, hepato- toxicity is the most frequent reason for drug withdrawal and is also the major cause of attrition in drug discovery/development. 2 6 7 8 Manifestations of liver injury can range from mild, asymptom- atic changes in serum transaminases, which occur at high fre- quency with a n