Table 6 shows the relationship between hepatic adverse events and combination of hepatic metabolism and average daily dose. It appears that compounds with both significant hepatic metabolism and average daily dose ≥50 mg (n = 50) are significantly more hepatotoxic than compounds belonging to other groups (Table 6).

When compared with compounds in all other groups combined, compounds with both significant hepatic metabolism and average daily dose ≥50 mg had significantly higher frequency of liver failure (P = 0.002), liver transplantation (P = 0.002), and fatal DILI (P = 0.003). When compared selleck kinase inhibitor with compounds in any other group separately, compounds with both significant hepatic metabolism and average daily dose >50 mg had a higher frequency of ALT >3 times the ULN (P = 0.01), liver failure (P = 0.001), liver transplantation (P = 0.08), and fatal DILI (P = 0.006) than other single group (Table 6).

The pathogenesis of idiosyncratic DILI is not well understood. Traditionally, it is thought to be unpredictable and not dose-dependent. However, in a recent study consisting of pharmaceutical Selleck ITF2357 databases, we have uncovered epidemiological signals to suggest that there may be a daily dose threshold (≥50 mg) beyond which oral medications have increased risk of serious DILI events.17 The current study was undertaken to examine the relationship between metabolism characteristics of medications and the risk of hepatic adverse events. Although some drugs are metabolized into stable metabolites, many drugs are transformed into unstable and potentially reactive metabolites that can bind to and attack hepatic macromolecules.19 Although reactive metabolites are considered to be of major importance in the pathogenesis of DILI, this has not been systematically investigated

previously for the overall risk for DILI. If this reactive metabolite theory is shown to be true for the overall risk for DILI, this is obviously of concern in the development of new drugs. We hypothesized that compounds with significant hepatic metabolism may potentially be more hepatotoxic due to the generation medchemexpress of reactive intermediaries and subsequent metabolic idiosyncrasy. Indeed, our epidemiological survey uncovered many associations between metabolic characteristics of medications and the risk of hepatic adverse events. This study is an extension of our previously published study that systematically examined the relationship between daily dose of oral medications and hepatic adverse events. Although the present study stems from the database and consists of the same set of oral compounds as our previous study, it addressed different hypotheses and uncovered key findings that have not been reported previously.