It is striking that none of the 12 compounds without any

hepatic metabolism had any identifiable reports of liver failure, liver transplantation, or fatal DILI. This does not necessarily mean that compounds without hepatic metabolism are entirely immune from hepatotoxicity, but it is significantly less likely. One example of a drug in which selective hepatic metabolism did not cause serious hepatotoxicity is ximelagatran, which was not approved by the Food and Drug Administration due to cases of hepatotoxicity during ABT-263 order its development.9–10 Because this medication was never approved for clinical use in the United States, it was not included in our study. Another example is pregabalin, which is also without hepatic metabolism but may be rarely associated with suspected severe hepatotoxicity.20 Because it was approved in December 2004, it was not included in our brand name compound category. Thus, lack of hepatic metabolism does not assure total lack of hepatotoxicity, but based on our data it indeed appears to be quite rare. According to the pharmacological interaction hypothesis, some drugs may be able to initiate an immune response through a reversible interaction with the major histocompatibility complex–T cell receptor complex.21 It has been postulated that ximelagatran leads

to hepatotoxicity by evoking an immune response by binding directly but reversibly to major histocompatibility Belinostat concentration complex.10 Second, we did not find a significant relationship between the frequency of hepatic adverse events and whether a compound is

metabolized by phase I and/or phase II reactions. Compounds with only phase II metabolism were not immune from hepatic adverse events. If confirmed, these observations are important, because they argue against a singular role for reactive metabolites 上海皓元 generated by phase I reactions in causing hepatotoxicity. Third, we found a statistically significant relationship between reports of jaundice and whether a compound has biliary excretion. Although it was not always clear from the reports contained within the DRUGDEX whether jaundice is hepatocellular or cholestatic in nature, we found that it was cholestatic in a substantial proportion. This leads us to speculate that compounds with biliary excretion may cause cholestatic jaundice in genetically predisposed individuals (e.g., defective transporters). There is increasing evidence that cholestatic liver injury associated with certain compounds results from a drug- or metabolite-mediated inhibition of hepatobiliary transport systems.22 Furthermore, we observed an additive effect of daily dose and hepatic metabolism; oral compounds with significant hepatic metabolism but also given at daily doses ≥50 mg had the highest risk of hepatic adverse drug reactions compared with other groups (Table 6).