Drug Metab Dispos 2020 11 17;48(11):1147-1160. Epub 2020 Sep 17.
Departments of Pharmacokinetics, Pharmacodynamics & Drug Metabolism (PPDM) (M.J.H., R.H., I.K., J.S., Q.C., R.E.), Genetics and Pharmacogenomics (K.Q.T.), and Safety Assessment and Laboratory Animal Resources (SALAR) (A.B., J.M., F.D.S.), Merck & Co., Inc., Kenilworth, New Jersey.
Hepatocellular accumulation of bile salts by inhibition of bile salt export pump (BSEP/) may result in cholestasis and is one proposed mechanism of drug-induced liver injury (DILI). To understand the relationship between BSEP inhibition and DILI, we evaluated 64 DILI-positive and 57 DILI-negative compounds in BSEP, multidrug resistance protein (MRP) 2, MRP3, and MRP4 vesicular inhibition assays. An empirical cutoff (5 μM) for BSEP inhibition was established based on a relationship between BSEP IC values and the calculated maximal unbound concentration at the inlet of the human liver (fu*I, assay specificity = 98%). Read More