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

J Pharm Sci. 2013 Sep;102(9):3037-57. doi: 10.1002/jps.23584. Epub 2013 May 7.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Bile Acids and Salts / metabolism*
  • Bile Ducts / drug effects
  • Bile Ducts / metabolism
  • Bile Ducts / pathology
  • Biological Transport / drug effects
  • Carrier Proteins / metabolism
  • Cholestasis / chemically induced*
  • Cholestasis / diagnosis
  • Cholestasis / metabolism*
  • Cholestasis / pathology
  • Humans
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Pharmaceutical Preparations / chemistry
  • Pharmaceutical Preparations / metabolism
  • Pharmacokinetics


  • Bile Acids and Salts
  • Carrier Proteins
  • Pharmaceutical Preparations