Scientific Publications by FDA Staff

Drug Metab Dispos 2014 Mar;42(3):318-22

The role of bile salt export pump gene repression in drug-induced cholestatic liver toxicity.

Garzel B, Yang H, Zhang L, Huang SM, Polli JE, Wang H

The bile salt export pump (BSEP, ABCB11) is predominantly responsible for the efflux of bile salts, and disruption of BSEP function is often associated with altered hepatic homeostasis of bile acids and cholestatic liver injury. Accumulating evidence suggests that many drugs can cause cholestasis through interaction with hepatic transporters. To date, a relatively strong association between drug-induced cholestasis and attenuated BSEP activity has been proposed. However, whether repression of BSEP transcription would contribute to drug-induced cholestasis is largely unknown. In this study, we selected 30 drugs previously reported as BSEP inhibitors to evaluate their effects on BSEP expression, farnesoid X receptor (FXR) activation, and correlations to clinically reported liver toxicity. Our results indicate that of the 30 BSEP inhibitors, five exhibited potent repression of BSEP expression (>/=60% repression), ten were moderate repressors (20-60% repression), whereas others had negligible effects (