1 Phase I reactions are catalyzed by the cytochrome P450 enzymes (CYPs) potentially leading to formation of reactive metabolites.1 The reactive drug metabolites generated through phase I reactions can potentially lead to liver injury, but phase II reactions are important in detoxifying these reactive metabolites.

BGJ398 cost These reactive metabolites or intermediates are in many instances metabolized further by phase II reactions that involve their conjugation with endogenous molecules such as glutathione, glucuronate, sulfate, or acetate in order to make them more water soluble and more easily eliminated from the body.1 Formation of toxic reactive metabolites has been suggested as potential mechanism for causing idiosyncratic drug-induced liver injury (DILI).2–5 Hepatic CYPs that generate reactive intermediates are largely concentrated in the centrilobular zone (zone III), an area that is predominantly affected in some forms of DILI (e.g., acetaminophen or halothane toxicity).6 These reactive metabolites may potentially bind to various cellular proteins and subsequently make them targets for immunomediated cell injury.5, 7 However, the role of phase II reactions in causing DILI cannot be excluded. A rodent

this website model suggested that diclofenac-adducts generated by glucuronidation may play an important role in the pathogenesis of diclofenac-induced liver injury, although evidence directly implicating its acyl-glucuronide derivative is lacking.8 Many experts believe that reactive metabolites play an important role in the pathogenesis of

DILI.2–5 find more If this theory was true, then compounds that are metabolized by the liver should have higher frequency of DILI than compounds without hepatic metabolism. However, some drugs without significant hepatic metabolism may cause serious DILI (e.g., ximelagatran).9, 10 We conducted a study to test the hypothesis that compounds with significant hepatic metabolism cause DILI at a greater frequency than compounds with lesser degrees of hepatic metabolism. Using two comprehensive pharmaceutical databases, we examined the relationship between hepatic metabolism of commonly prescribed medications and their reported ability to cause hepatotoxicity. ALT, alanine aminotransferase; CYP, cytochrome P450 enzyme; DILI, drug-induced liver injury; ULN, upper limit of normal. A widely available pharmaceutical database (www.drugtopics.com) was used to generate the names of the top 200 brand and top 200 generic medications by prescription volume in the United States for the year 2005.11, 12 Only oral medications were included, and compounds listed in both the brand and generic lists were considered one entry. Entries with more than one active compound (i.e., fixed drug formulations) and those containing acetaminophen compounds were excluded. These criteria identified 207 individual compounds that were considered eligible for inclusion in this study.