Journal
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 54
Volume 54, Issue -, Pages 509-535Publisher
ANNUAL REVIEWS
DOI: 10.1146/annurev-pharmtox-011613-140021
Keywords
drug-drug interactions; transporter regulation; transporter trafficking; transporter multiplicity; intracellular unbound concentration; sandwich-cultured hepatocytes
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Funding
- NIEHS NIH HHS [T32 ES007126] Funding Source: Medline
- NIGMS NIH HHS [R01 GM41935, R01 GM041935] Funding Source: Medline
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Hepatic efflux transporters include numerous well-known and emerging proteins localized to the canalicular or basolateral membrane of the hepatocyte that are responsible for the excretion of drugs into the bile or blood, respectively. Altered function of hepatic efflux transporters due to drug-drug interactions, genetic variation, and/or disease states may lead to changes in xenobiotic exposure in the hepatocyte and/or systemic circulation. This review focuses on transport proteins involved in the hepatocellular efflux of drugs and metabolites, discusses mechanisms of altered transporter function as well as the interplay between multiple transport pathways, and highlights the importance of considering intracellular unbound concentrations of transporter substrates and/or inhibitors. Methods to evaluate hepatic efflux transport and predict the effects of impaired transporter function on systemic and hepatocyte exposure are discussed, and the sandwich-cultured hepatocyte model to evaluate comprehensively the role of hepatic efflux in the hepatobiliary disposition of xenobiotics is characterized.
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