Descriptive statistics Roscovitine in vitro such as the mean plus standard deviation and percentages were used to characterize the cohort. Categorical variables were tested for statistical significant differences by way of the chi-square or Fisher’s exact test and continuous variables by way of the Student t test; P < 0.05 was considered statistically significant. Out of 207 eligible compounds, 149 belonged to the significant hepatic metabolism group and 55 to the nonsignificant hepatic metabolism group (Supporting Table 1). There were three compounds for which the details of their metabolism could

not be identified (docusate, dicyclomine, nitrofurantoin). The mean number of prescriptions written for the significant hepatic metabolism group was 7,954,705 and was not statistically different from the nonsignificant buy MG-132 hepatic metabolism group (9,068,470, P = 0.5). Thirty-six percent of the compounds

in the significant hepatic metabolism group had an average daily dose of ≥50 mg versus 51% of the compounds in the nonsignificant hepatic metabolism group (P = 0.03). Compared with compounds without significant hepatic metabolism, compounds in the significant hepatic metabolism group were significantly more likely to have reports of ALT ≥3 times the ULN (35% versus 11%, P = 0.001), liver failure (28% versus 9%, P = 0.004), and fatal DILI (23% versus 4%, P = 0.001), but not liver transplantation (9% versus 2%, P = 0.11) or jaundice (46% versus 35%, P = 0.2) (Table 1). Compared with compounds metabolized only through phase I reactions, compounds metabolized through both phase I and II reactions

did not have greater frequency of jaundice (P = 0.74), liver failure (P = 0.36), liver transplantation (P = 0.36), or fatal DILI (P = 0.56), but had significantly higher reports of ALT >3 times the ULN (45% versus 28%, P = 0.03) (Table 2). There were nine compounds with metabolism only through phase II reactions; of these, one had ALT >3 times the ULN, four had jaundice, two had liver failure, one caused liver transplantation, and two caused fatal DILI (Table 2). These nine compounds were levothyroxine, MCE telmisartan, metoclopramide, hydralazine, prednisolone, topiramate, labetalol, and niacin. There were 50 compounds with documented biliary excretion of the parent compound or its active metabolite. When compared with those without biliary excretion, compounds with biliary excretion had significantly higher frequency of jaundice (74% versus 40%, P = 0.0001) but not other hepatic adverse events (Table 3). Table 4 shows the relationship between hepatic adverse events and metabolism through four common CYPs. There are potentially significant differences among different CYP pathways and reports of liver failure and fatal DILI. In general, CYP2C9 and CYP2C19 pathways appeared more toxic than CYP3A and CYP2D6 (Table 4). There were 12 compounds without any hepatic metabolism (Table 5).