BILE ACID TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 203

HEPATOCYTE

Na +

BSEP

NTCP

MRP2

OATP1B1

MRP3
MRP4

MDR3
ABCG5 /
ABCG8

OST α /
OST β

I-BABP

ASBT

Na +

Na +

ILEOCYTE

FIGURE 9.1. Transporters involved in the enterohepatic circulation of bile acids and bile
formation. Bile acids are taken up into the ileocyte from the intestinal lumen by the sodium-
dependent transporter ASBT, and putatively trafficked through the ileocyte by I-BABP. Bile
acids are effluxed from the ileocyte to portal venous blood by the action of the OST /OST
heterodimer. At the basolateral membrane of the hepatocyte the main bile acid uptake system is
NTCP, which transports bile acids from portal blood in a sodium-dependent manner. OATP1B1
may also contribute to hepatic bile acid uptake in a sodium-independent manner. In normal
conditions, very little, if any, bile acids are effluxed back to portal blood at the basolateral
membrane of hepatocytes. However, in states of cholestasis, expression of the bile acid spillover
pumps MRP3 and MRP4 is increased, and they may mediate efflux of bile acids into systemic
circulation. The main efflux system for bile acids from hepatocytes into bile is BSEP at the
canalicular hepatocyte membrane. In addition, MRP2 may also export divalent and sulphated
or glucuronidated bile acids into bile. MDR3 and the ABCG5/ABCG8 heterodimer transport
phospholipids and cholesterol, respectively, from hepatocytes into bile.

well as other conjugated anions, such as chemotherapeutic agents and antibiotics, into
bile. 6 MRP2 is also a member of the ABC transporter family which is located at the
canalicular membrane of hepatocytes.
In addition to BSEP and MRP2, other transporters localized at the canalicular mem-
brane of hepatocytes are involved in bile formation. Bile acids are the most prominent
(60 to 70%) solid component of bile, but hepatic bile also contains phospholipids,