Abstract
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 (80μM) 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 20μM, respectively. This simplified model provides a tool for a first indication whether drugs at therapeutic concentrations might cause cholestasis by inhibiting BSEP.
Highlights
Drug-induced liver injury (DILI) is a major cause for drug withdrawal from the market
For bile salt export pump (BSEP) transport studies, we used vesicles isolated from HEK293 cells over-expressing BSEP and compared the data to those obtained with control vesicles containing Enhanced Yellow Fluorescent Protein (EYFP)
We developed a mechanistic biokinetic model of hepatocyte bile acid handling based on human in vitro data (Fig. 3), which simulates intrahepatic bile acid concentrations in the absence and presence of cholestatic drugs
Summary
Drug-induced liver injury (DILI) is a major cause for drug withdrawal from the market. Several transporters are involved in the hepatocellular transport of bile acids. Multidrug resistance related proteins 3 and 4 (MRP3, ABCC3; MRP4, ABCC4) and the organic solute transporter (OSTα/β; SLC51A/SLC51B) are considered to be involved in sinusoidal efflux (Dawson et al, 2009), which is low under normal physiological conditions. The canalicular efflux transporter bile salt export pump (BSEP) seems to be the key player in the development of cholestatic DILI. This has been summarized by Vinken et al in an Adverse Outcome Pathway (AOP), and further confirmed by Woodhead et al by sensitivity analysis of a mechanistic model of cholestatic DILI (Vinken et al, 2013; Woodhead et al, 2014)
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