An updated review on drug-induced cholestasis: mechanisms and investigation of physicochemical properties and pharmacokinetic parameters

Abstract

Drug-induced cholestasis is an important form of acquired liver disease and is associated with significant morbidity and mortality. Bile acids are key signaling molecules, but they can exert toxic responses when they accumulate in hepatocytes. This review focuses on the physiological mechanisms of drug-induced cholestasis associated with altered bile acid homeostasis due to direct (e.g., bile acid transporter inhibition) or indirect (e.g., activation of nuclear receptors, altered function/expression of bile acid transporters) processes. Mechanistic information about the effects of a drug on bile acid homeostasis is important when evaluating the cholestatic potential of a compound, but experimental data often are not available. The relationship between physicochemical properties, pharmacokinetic parameters, and inhibition of the bile salt export pump among 77 cholestatic drugs with different pathophysiological mechanisms of cholestasis (i.e., impaired formation of bile vs. physical obstruction of bile flow) was investigated. The utility of in silico models to obtain mechanistic information about the impact of compounds on bile acid homeostasis to aid in predicting the cholestatic potential of drugs is highlighted.

Keywords: bile acid; drug-induced cholestasis; in silico modeling; pharmacokinetic parameters; physicochemical properties; transporters.

Figure 1

Localization of bile acid transporters in human hepatocytes (A) and enterocytes (B).

Figure 2. Mechanisms of altered bile acid transport by cholestatic drugs. (A) Direct inhibition of transport proteins

Cholestatic drugs might directly interfere with bile acid transport through inhibition of transporter function. (B) Altered localization of transport proteins. Certain cholestatic drugs can activate membrane-bound and intracellular receptors resulting in activation or inhibition of intracellular signal transduction and increased insertion into or internalization from the plasma membrane. Internalized proteins can be degraded or undergo recycling to the plasma membrane. (C) Altered transport protein expression. Bile acids and certain cholestatic drugs are activators of nuclear receptors (NR). Binding of ligands results in dissociation of heat-shock proteins from the NR, homo-dimerization and subsequent translocation to the nucleus where they bind to response elements of target genes and activate gene transcription.