Transporter-mediated hepatocyte uptake

Explain the role of sinusoidal transport on hepatic clearance, and list the various transporters that mediate drug uptake into the hepatocyte. 

FIGURE 2-2 Hepatic drug transporters. Membrane transporters, shown as hexagons with arrows, work in concert with phase 1 and phase 2 drug-metabolizing enzymes in the hepatocyte to mediate the uptake and efflux of drugs and their metabolites. 

Nakai, D., et al. Human liver-specific organic anion transporter, LST-1, mediates uptake of pravastatin by human hepatocytes. J. Pharmacol. Exp. Ther. 2001, 297, 861-867. 

The liver plays an important role in determining the oral bioavailability of drags. Drag molecules absorbed into the portal vein are taken up by hepatocytes, and then metabolized and/or excreted into the bile. For hydrophilic drugs, transporters located on the sinusoidal membrane are responsible for the hepatic uptake [1, 2]. Biliary excretion of many drags is also mediated by the primary active transporters, referred to as ATP-binding cassette transmembrane (ABC) transporters, located on the bile canalicular membrane [1, 3-5], Recently, many molecular biological... 

Figure 15.1 Schematic illustration of the extended phase concept during drug elimination in the kidney and liver. Phase 0 = uptake of drugs from the blood into the hepatocytes or proximal tubule epithelial cells. This uptake is mediated by transport proteins belonging to the SLC (solute carrier) transporter superfamily. Phase I and...

Hepatocytes are the dominant cell type in the Hver constituting approx. 70% of all hver cells. They are responsible for the uptake of substances from the blood and for the excretion by the bihary system. Specific requirements have to be met by compounds to be able to enter the hepatocytes. These are definite ranges of molecular weight, lipophiHcity and polarity or charge. Additionally, receptor-mediated transport systems of the hepatocytes pose further requirements on the structure of the substance. 

---