Effect of Liver Disease on Hepatic Transporter Expression and Function

Abstract

Liver disease can alter the disposition of xenobiotics and endogenous substances. Regulatory agencies such as the Food and Drug Administration and the European Medicines Evaluation Agency recommend, if possible, studying the effect of liver disease on drugs under development to guide specific dose recommendations in these patients. Although extensive research has been conducted to characterize the effect of liver disease on drug-metabolizing enzymes, emerging data have implicated that the expression and function of hepatobiliary transport proteins also are altered in liver disease. This review summarizes recent developments in the field, which may have implications for understanding altered disposition, safety, and efficacy of new and existing drugs. A brief review of liver physiology and hepatic transporter localization/function is provided. Then, the expression and function of hepatic transporters in cholestasis, hepatitis C infection, hepatocellular carcinoma, human immunodeficiency virus infection, nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, and primary biliary cirrhosis are reviewed. In the absence of clinical data, nonclinical information in animal models is presented. This review aims to advance the understanding of altered expression and function of hepatic transporters in liver disease and the implications of such changes on drug disposition.

Keywords: ABC transporters; hepatic transport; hepatobiliary disposition; hepatocytes; pharmacokinetics.

Figure 1. Immunofluorescence staining of MRP1 in a liver tissue section from a patient with primary biliary cirrhosis

Dual staining of MRP1 (red) and Na⁺/K⁺ ATPase (green), which was used as a basolateral membrane marker. The nuclei are stained in blue. The general methods are described in Pomozi et al. MRP1 and Na⁺/K⁺ ATPase antibodies were purchased from Abcam and SantaCruz Biotechnology, respectively.