Abstract
Inhibition of the activity of the bile salt export pump (human BSEP: ABCB11) has been proposed to play a role in drug induced liver injury (DILI). To enhance understanding of the relationship between BSEP inhibition and DILI, inhibition of human BSEP (hBSEP) and its rat orthologue (rBsep) by 85 pharmaceuticals was investigated in vitro. This was explored using assays that quantified inhibition of ATP-dependent [3H] taurocholate uptake into inverted plasma membrane vesicles from Sf21 insect cells which expressed the proteins. 40 pharmaceuticals exhibited evidence of in vitro transporter inhibition and overall a close correlation was observed between potency values for inhibition of hBSEP and rBsep activity (r2 = 0.94), although 12 drugs exhibited >2-fold more potent inhibition of hBSEP than rBsep. The median potency of hBSEP inhibition was higher amongst drugs that caused cholestatic/mixed DILI than amongst drugs which caused hepatocellular or no DILI, as was the incidence of hBSEP inhibition with IC50 <300 μM. All drugs with hBSEP IC50 <300 μM had molecular weight >250 Da, ClogP >1.5 and non-polar surface area (NPSA) >180Å. A clear distinction was not evident between hBSEP IC50, unbound plasma concentration (Cmax,u) of the drugs in man, and whether or not the drugs caused DILI. However, all 17 of the drugs with hBSEP IC50 <100 μM and Cmax,u >0.002 μM caused DILI. Overall, these data indicate that inhibition of hBSEP/rBsep correlates with the propensity of numerous pharmaceuticals to cause cholestatic DILI in man and is associated with several of their physicochemical properties.
- ABC transporters
- bile acid transport
- hepatobiliary transport
- hepatotoxicity
- idiosyncratic drug reactions
- liver injury
- transporters
- Received May 31, 2011.
- Accepted September 30, 2011.
- The American Society for Pharmacology and Experimental Therapeutics