Bile salt export pump inhibition

Bile salt export pump (BSEP gene symbol ABCB11) mediates the biliary excretion of nonconjugated bile salts, such as taurocholic acid, glycocholic acid and cholic acid, and therefore is responsible for the formation of the bile acid-dependent bile flow [97, 98]. Its hereditary defect results in the acquisition of PFIC2, a potentially lethal disease which requires liver transplantation [17, 81, 82, 99]. As discussed in Section 12.5.2, the inhibition of BSEP following drug administration may result in cholestasis. 

Fattinger, K., Funk, C., Pantze, M., Weber, C., Reichen, J., Stieger, B., Meier, P. J., The endothelin antagonist bosentan inhibits the canalicular bile salt export pump a potential mechanism for hepatic... 

J., Kuliak-Ublick, G. A., Meier, P. J., Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver, Gastroenterology 2000, 118, 422-430. 

Mita, S. et al. (2006) Inhibition ofbile add transport across Na + /taurocholate cotransporting polypeptide (SLClOAl) and bile salt export pump (ABCB 11)-coexpressing LLC-PKl cells by cholestasis-inducing drugs. Drug Metabolism and Disposition The Biological Fate of Chemicals, 34 (9), 1575-1581. 

Funk, C. et al. (2001) Troglitazone-induced intrahepatic cholestasis by an interference with the hepatobiliary export ofbile acids in male and female rats. Correlation with the gender difference in troglitazone sulfate formation and ihe inhibition of the canalicular bile salt export pump (Bsep) by troglitazone and troglitazone sulfate. Toxicology, 167 (1), 83-98. 

Fattinger K, Funk C, Pantze M, Weber C, Reichen J, Stieger B, Meier PJ. The endothehn antagonist bosentan inhibits the canahcular bile salt export pump a potential mechanism for hepatic adverse reactions. Clin Pharmacol Ther 2001 69(4) 223-31. 

H., and Ishikawa, T. (2007) Prediction of drug-induced intrahepatic cholestasis in vitro screening and QSAR analysis of drugs inhibiting the human bile salt export pump. Expert Opinion on Drug Safety, 6, 71-86. 

Troglitazone sulfate (Ml, the main metabolite) undergoes biliary excretion and accounts for up to 85% of the dose in humans (Loi et al. 1999). In patients with hepatic impairment, troglitazone sulfate was found to accumulate about fourfold in plasma with a threefold increased half-life (Ott et al. 1998 Loi et al. 1999). This metabolite also inhibited the canalicular bile salt export pump (Bsep), organic anion transporting polypeptide (OATP) transporters as well as drug transporters, suggesting it contributes to the hepatotoxicity. 

Pure cholestasis without hepatitis is observed most frequently with contraceptives and 17a-alkylated androgenic steroids, and the mechanism most likely involves interference with hepatocyte canalicular efflux systems for bile salts, organic anions, and phospholipids. The rate-limiting step in bile formation is considered to be the bile salt export pump (BSEP)-mediated translocation of bile salts across the canalicular hepatocyte membrane. Inhibition of BSEP function by metabolites of cyclosporine A, troglitazone, bosentan, rifampicin, and sex steroids is an important cause of drug induced cholestasis (Kullak-Ublick, 2004). 

Another ABC transporter is sister P-glycoprotein, otherwise called the bile salt export pump (BSEP or ABCBl 1). It has been suggested that inhibition of this pump may increase the risk of cholestasis, see Drug transporters under Drug excretion interactions , (p.7). 

Aleo, M., Luo, Y., Swiss, R., Bonin, P.D., Potter, D.M., Will, Y. (2014). Human drug-induced liver injury severity is highly associated with dual inhibition of mitochondrial function and bile salt export pump. Hepatology, 60,1015-1022. 

Dawson, S., Stahl, S., Paul, N., Barber, J., and Kenna, J.G. (2012) In vitro inhibition of the bile salt export pump correlates with risk of cholestatic drug-induced liver injury in humans. Drug Metab. Dispos., 40, 130-138. 

Rodrigues AD, Lai Y, Cvijic ME, EUdn LL, Zvyaga T, Soars MG (2014). Drug-induced perturbations of the bile acid pool, cholestasis, and hepatotoxicity mechanistic considerations beyond the direct inhibition of the bile salt export pump. Drug Metab Dispos 42, 566-74. 

Warner DJ, Chen H, Cantin LD, Kenna JG, Stahl S, Walker CL, Noeske T (2012) Mitigating the inhibition of human bile salt export pump by drugs opportunities provided by physicochemical property modulation, in silico modeling, and structural modification. Drug Metab Dispos 40, 2332-41. 

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