[Frontiers in Bioscience 14, 4257-4280, January 1, 2009]

Hepatobiliary transporters in the pharmacology and toxicology of anticancer drugs

Jose J.G. Marin1, Oscar Briz2, Maria J. Perez2, Marta R. Romero1, Maria J. Monte1

1Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), 2Research Unit, University Hospital, University of Salamanca, CIBERehd, Spain

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Hepatobiliary transport of anticancer drugs
3.1. Transporters involved in the liver uptake of antineoplastic drugs
3.1.1. OATPs (SLCO family)
3.1.2. NTCP and ASBT (SLC10A family)
3.1.3. OATs (SLC22A family)
3.1.4. OCTs and OCTNs (SLC22A family)
3.1.5. Nucleoside transporters CNTs and ENTs (SLC28 and SLC29 families)
3.1.6. Other transport systems involved in the uptake of antineoplastic drugs
3.2. Transporters involved in the export of anticancer drugs by liver cells
3.2.1. The ABCA family
3.2.2. The ABCB family
3.2.3. The ABCC family
3.2.4. The ABCG family
4. Changes in the function of biliary transporters induced by interactions with anticancer drugs
4.1. Drug-drug interactions
4.2. Drug-nutrient interactions
4.3. Interactions between drugs and endogenous compounds
5. Effect of anticancer drugs on the expression of hepatobiliary transporters
6. Expression of hepatobiliary transporters in tumors of the enterohepatic circuit
7. Targeting of cytostatic drugs using hepatobiliary transporters
8. Acknowledgment
9. References

1. ABSTRACT

The existence of carrier proteins located in the basolateral and apical membranes of hepatocytes, cholangiocytes and epithelial cells of the ileal mucosa, together with their more or less broad substrate specificities -implying their ability to transport many different drugs, including anticancer drugs- has important pharmacological repercussions. These vary from the existence of interactions of drugs with endogenous and xenobiotic substances to the possibility of using these transporters in the targeting of drug delivery systems, which can be useful either to direct anticancer drugs towards tumors located in the hepatobiliary system or to facilitate their hepatobiliary excretion. This justifies the growing interest in bile acid derivatives as targeted pharmacological tools, in general, and in anticancer chemotherapy, in particular. Moreover, interactions of antitumor drugs with hepatobiliary transporters may account for the appearance of toxic side effects associated with the use of these drugs. The present review covers these aspects of the pharmacology and toxicology of hepatobiliary transport systems in relation to anticancer drugs.