Drug-induced liver injury is an important reason for drug candidate failure. Alterations in the hepatobiliary disposition of bile acids are a proposed mechanism of cholestatic hepatotoxicity. Bile acids are synthesized in the hepatocyte, and excreted into the bile primarily by the bile salt export pump. Therefore, inhibition of the bile salt export pump by drugs has been postulated as a risk factor in the development of cholestatic hepatotoxicity. However, recent publications have shown a lack of correlation between bile salt export pump inhibition potency and drug-induced liver injury incidence. Following inhibition of the bile salt export pump mediated efflux of bile acids, the liver compensates through various mechanisms (adaptive response) including upregulation of basolateral bile acid efflux mediated by the farnesoid X receptor, the master regulator of bile acid homeostasis. The C-DILI™ assay integrates the effects of bile salt export pump inhibition, farnesoid X receptor antagonism, and basolateral efflux inhibition of bile acids to more accurately predict a drug's potential to cause cholestatic hepatotoxicity and drug-induced liver injury.
Keywords: Adaptive response; BSEP—Bile salt export pump; Bile acid transport; Cholestatic hepatotoxicity; Compensatory mechanism; DILI—Drug-induced liver injury; FXR—Farnesoid X receptor; MRP—Multidrug resistance-associated protein; OST—Organic solute and steroid transporter; Primary hepatocyte culture; SCHH—Sandwich-cultured human hepatocytes; Transporter Certified™; efflux transport.