From: Methods in Molecular Biology, vol. 448, Pharmacogenomics in Drug Discovery and Development Edited by Q. Yan © Humana Press, Totowa, NJ

with influx or efflux via active transport. As such, these transporters can significantly affect drug disposition. For example, influx of a drug from the blood to the liver, where it is subsequently metabolized and excreted, may increase the rate of elimination. These proteins and the genes that encode them are essential to drug uptake, bioavailability, targeting, efficacy, toxicity, and clearance. The genes encoding these transporters are polymorphic—phenotypically resulting in transporters with different expression levels and transport efficiency. Consequently, polymorphisms in transporters are often responsible for some variability in drug pharma-cokinetics and response to treatment.

Many drugs undergo transport that is mediated by the adenosine triphosphate (ATP)-binding cassette (ABC) family of transporters. There are a total of 48 known ABC genes, including ABCB1 (P-glycoprotein, multidrug resistance [MDR] 1), ABCC1 (MRP1), and ABCG2 (BCRP, MXR, ABCP), all of which utilize ATP to move substrates across membranes (1-3). These transporters generally limit drug uptake through the intestinal wall, move substrates out of tissues into the systemic circulation, and eventually mediate the clearance of drugs from the body. The ABC family of proteins are known as efflux transporters and move substrates across the cell membrane, out of the cell.

The most characterized polymorphic transporters to date are ABCB1 and ABCG2 (4). Many current drugs approved by the Food and Drug Administration (FDA) are substrates of these transporters, although both transporters also efflux a plethora of other compounds, including naturally occurring toxins. ABCB1 and ABCG2 are expressed in the enterocytes, colon, intestinal epithelium, canalicular plasma membrane of hepatocytes, and proximal renal tubule (5-9). ABCB1 and ABCG2 play a role in drug uptake, distribution, and elimination at these sites, and thus they often mediate bioavailability and exposure to their substrate drugs, as mentioned in Table 4.1 (10,11). In addition, ABCB1 and ABCG2 have been shown to be expressed in hematologic tissues, including hematopoietic stem cells, and endothelial cells composing blood-tissue barriers of the brain, heart, nerves, testes, and placenta, where they efflux substrates out of these tissues into the systemic circulation (6,12-17). An exception includes the expression of ABCB1 in the choroid plexus, where it transports molecules from the circulation into the cerebro-spinal fluid (16,18). It is believed that the evolutionary role of these transporters is to limit the penetration of toxic molecules into critical organs, thereby serving a protective role in blood-tissue barriers.

Two other efflux transporters, ABCC1 and ABCC2 (MRP2) are also involved in drug disposition. ABCC1 is expressed ubiquitously and is localized to the basolateral, rather than apical, membranes of epithelial cells. Because of its basolateral localization, ABCC1 pumps drugs into the body rather than into the bile, urine, or intestine. For this reason, it is thought to serve mainly as a protective barrier in epithelial cells of tissues rather than as a classic drug efflux pump (19). ABCC2 is similar in function to ABCB1. It is expressed on the apical domain of epithelial cells and is involved in luminal excretion in organs such as liver, intestine, and kidney but also serves a role in blood-tissue barriers (20). Both ABCC1 and ABCC2 primarily secrete drugs that

Table 4.1 Selected substrates of ABCB1, ABCG2, ABCC1, ABCC2, OATP1B1, and OATP1B3


Transporter substrates and inhibitors

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