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Role of the Intestinal Bile Acid Transporters in Bile Acid and Drug Disposition

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Book cover Drug Transporters

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 201))

Abstract

Membrane transporters expressed by the hepatocyte and enterocyte play critical roles in maintaining the enterohepatic circulation of bile acids, an effective recycling and conservation mechanism that largely restricts these potentially cytotoxic detergents to the intestinal and hepatobiliary compartments. In doing so, the hepatic and enterocyte transport systems ensure a continuous supply of bile acids to be used repeatedly during the digestion of multiple meals throughout the day. Absorption of bile acids from the intestinal lumen and export into the portal circulation is mediated by a series of transporters expressed on the enterocyte apical and basolateral membranes. The ileal apical sodium-dependent bile acid cotransporter (abbreviated ASBT; gene symbol, SLC10A2) is responsible for the initial uptake of bile acids across the enterocyte brush border membrane. The bile acids are then efficiently shuttled across the cell and exported across the basolateral membrane by the heteromeric Organic Solute Transporter, OSTα–OSTβ. This chapter briefly reviews the tissue expression, physiology, genetics, pathophysiology, and transport properties of the ASBT and OSTα–OSTβ. In addition, the chapter discusses the relationship between the intestinal bile acid transporters and drug metabolism, including development of ASBT inhibitors as novel hypocholesterolemic or hepatoprotective agents, prodrug targeting of the ASBT to increase oral bioavailability, and involvement of the intestinal bile acid transporters in drug absorption and drug–drug interactions.

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Abbreviations

ABC:

ATP-binding cassette

ASBT:

Apical-dependent bile acid transporter

BA:

Bile acid

BARI:

Bile acid reabsorption inhibitor

BCRP:

Breast cancer resistance protein

BDDCS:

Biopharmaceutics Drug Disposition Classification System

BLM:

Basolateral membrane

BSEP:

Bile salt export pump

CHO:

Chinese hamster ovary

CM:

Canalicular membrane

FDA:

United States Food and Drug Administration

FGF:

Fibroblast growth factor

FHTG:

Familial Hypertriglyceridemia

FXR:

Farnesoid X-receptor

GWAS:

Genome-Wide Association Study

IBAM:

Idiopathic bile acid malabsorption

ILBP:

Ileal lipid binding protein

LDL:

Low density lipoprotein

MDCK:

Madin-Darby canine kidney

MDR:

Multidrug resistance protein

MRP:

Multidrug resistance-associated protein

norUDCA:

Nor-ursodeoxycholic acid

NTCP:

Na+-taurocholate cotransporting polypeptide

OATP:

Organic anion transporting polypeptide

OMIM:

Online Mendelian Inheritance in Man

OST:

Organic solute transporter

PBAM:

Primary bile acid malabsorption

POSCH:

Program on the Surgical Control of Hyperlipidemias

PSC:

Primary Sclerosing Cholangitis

QSAR:

Quantitative structure–activity relationship

SLC:

Solute carrier

SNP:

Single nucleotide polymorphism

UDCA:

Ursodeoxycholic acid

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Acknowledgments

PAD was supported by the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) grant DK047987 and an American Heart Association Mid-Atlantic Affiliate Grant-in-aid. The author thanks Dr. Anuradha Rao for assistance with the figures, valuable suggestions, and critical reading of the manuscript.

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  1. Department of Internal Medicine, Section on Gastroenterology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA

    Paul A. Dawson

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  1. Inst. Experimentelle und Klinische, Pharmakologie und Toxikologie, Universität Erlangen-Nürnberg, Fahrstr. 17, Erlangen, 91054, Germany

    Martin F. Fromm

  2. Division of Clinical Pharmacology, University of Western Ontario, Windmere Road 339, London, N6A 5A5, Ontario, Canada

    Richard B. Kim

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Dawson, P.A. (2011). Role of the Intestinal Bile Acid Transporters in Bile Acid and Drug Disposition. In: Fromm, M., Kim, R. (eds) Drug Transporters. Handbook of Experimental Pharmacology, vol 201. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-14541-4_4

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