Abstract
Bardoxolone methyl, also known as CDDO-Me or RTA 402, was a new investigational drug that improves the estimated glomerular filtration rate by activating the Keap1-Nrf2 pathway. Bardoxolone methyl is a synthetic triterpenoid compound derived from oleanolic acid (OA). OA-mediated cholestasis has not been reported in the clinical treatment of treat liver disorders but has been reported in mice. Cholestasis can be transient (e.g., during pregnancy) but can also be chronic and is a risk factor for hepatobiliary carcinoma. Therefore, it is important to evaluate and understand the risk of drug-induced cholestasis and its mechanisms, including species differences. We evaluated the effects of bardoxolone methyl on the in vivo hepatobiliary systems in rats and monkeys, as well as sandwich-cultured hepatocytes. Bardoxolone methyl was administered daily to rats and monkeys for 26 or 52 weeks, respectively. As a result, bardoxolone methyl was associated with the development of cholestasis and cholangioma in rats but not in monkeys. In an in vitro evaluation using sandwich-cultured hepatocytes treated with bardoxolone methyl, cholestasis was observed in rat hepatocytes, but not in monkey or human hepatocytes. A gene expression analysis showed that rat-specific cholestasis was caused by the reduction of the bile salt export pump gene expression after treatment with bardoxolone methyl. These results strongly suggest that the effects of bardoxolone methyl on the hepatobiliary system differ among animal species, especially between rodents and non-rodents. In conclusion, the risk of cholestasis and cholestasis-derived carcinogenicity associated with bardoxolone methyl are expected to be quite low in humans.
