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Development of a mechanistic biokinetic model for hepatic bile acid handling to predict possible cholestatic effects of drugs

Author: Notenboom, S. · Weigand, K.M. · Proost, J.H. · Lipzig, M.M.H. van · Steeg, E. van de · Broek, P.H.H. van den · Greupink, R. · Russel, F.G.M. · Groothuis, G.M.M.
Source:European Journal of Pharmaceutical Sciences, 115, 175-184
Identifier: 784883
doi: doi:10.1016/j.ejps.2018.01.007
Keywords: Biology · Bile acid handling · Biokinetic model · BSEP · Cholestasis · Human · In silico · NTCP · Biomedical Innovation · Healthy Living · Life Triskelion BV · MSB - Microbiology and Systems Biology ADME - ADME/DMPK · ELSS - Earth, Life and Social Sciences TNO Bedrijven


Drug-induced liver injury (DILI) is a common reason for drug withdrawal from the market. An important cause of DILI is drug-induced cholestasis. One of the major players involved in drug-induced cholestasis is the bile salt efflux pump (BSEP; ABCB11). Inhibition of BSEP by drugs potentially leads to cholestasis due to increased (toxic) intrahepatic concentrations of bile acids with subsequent cell injury. In order to investigate the possibilities for in silico prediction of cholestatic effects of drugs, we developed a mechanistic biokinetic model for human liver bile acid handling populated with human in vitro data. For this purpose we considered nine groups of bile acids in the human bile acid pool, i.e. chenodeoxycholic acid, deoxycholic acid, the remaining unconjugated bile acids and the glycine and taurine conjugates of each of the three groups. Michaelis-Menten kinetics of the human uptake transporter Na+-taurocholate cotransporting polypeptide (NTCP; SLC10A1) and BSEP were measured using NTCP-transduced HEK293 cells and membrane vesicles from BSEP-overexpressing HEK293 cells. For in vitro-in vivo scaling, transporter abundance was determined by LC-MS/MS in these HEK293 cells and vesicles as well as in human liver tissue. Other relevant human kinetic parameters were collected from literature, such as portal bile acid levels and composition, bile acid synthesis and amidation rate. Additional empirical scaling was applied by increasing the excretion rate with a factor 2.4 to reach near physiological steady-state intracellular bile acid concentrations (80 μM) after exposure to portal vein bile acid levels. Simulations showed that intracellular bile acid concentrations increase 1.7 fold in the presence of the BSEP inhibitors and cholestatic drugs cyclosporin A or glibenclamide, at intrahepatic concentrations of 6.6 and 20 μM, respectively. This simplified model provides a tool for a first indication whether drugs at therapeutic concentrations might cause cholestasis by inhibiting BSEP. © 2018 The Authors