This chapter provides our current understanding of transporter types,
methods involved in the assessment of their function, and examples of
transporter substrates and inhibitors causing changes in pharmacokinetics and/
or pharmacodynamics of various drugs in animal models and/or humans. This
should not be considered as an exclusive review but rather an updated
understanding. References are provided for some of the past reviews in this
area for extended reading.
Classically, transporters are proteins that translocate endogenous com-
pounds (such as bile acids, lipids, sugars, amino acids, steroids, hormones, and
electrolytes) and xenobiotics (such as drugs and toxins) across biological
membrane to maintain cellular and physiologic solute concentrations and fluid
balance as well as to provide a mechanism of detoxification for any potentially
harmful foreign substances in cells. Transporter proteins are divided into the
adenosine triphosphate (ATP)-binding cassette (ABC) transporter superfamily
and the solute carrier (SLC) family of proteins. SLC transporters act by
facilitating the uptake of their substrates into the cells. This family of
transporters contains 46 subfamilies and 360 transporters including sodium-
bile acid cotransporters (NTCP, SLC10 family), proton oligopeptide cotran-
sporters (PEPT, SLC15 family), organic anion transporting polypeptides
(OATP, SLC21 family), organic cation/anion/zwitterion transporters (OCT/
OAT, SLC22 family), and nucleoside transporters (NT, SLC29 family). SLC
transporters are divided into facilitative transporter and active transporter
classes. Facilitative transporters are not coupled to any energy source and
passively facilitate the diffusion of molecules across the membrane down their
concentration gradients allowing a rapid equilibrium across the membrane.
The active SLC transporters use an energy source that is provided by an ion-
exchanger that causes pH alteration in the microenvironment of the cell
surface, or is indirectly coupled to Na+/K+ ATPase that can create an
intracellular negative membrane potential due to the imbalance in charge
movement. ABC efflux membrane transporters consist of transmembrane
domains (TMDs) and nucleotide binding domains (NBDs). They are directly
coupled to ATPase activity and hydrolyze ATP to derive energy for pumping
substrates across the cell membrane. The full efflux transporters, such as P-
glycoprotein (P-gp) and multidrug resistance protein (MRP), possess two
NBDs in one polypeptide chain. The half transporters, such as breast cancer
resistance protein (BCRP), only contain one NBD (Borst and Elferink, 2002).
The half transporters function as a dimer or tetramer bridged by specific
linkages. Among 49 human genes in seven subfamilies of ABC transporters,
P-gp (also known as multidrug resistance 1 (MDR1) protein) in ABCB family,
MRP1 and MRP2 in ABCC family and BCRP (also known as mitoxantrone
resistance protein (MXR), ABCG2, ABCP) in ABCG family are the major
ABC transporters to confer resistance in the tumor cells and to efflux
xenobiotics (such as drugs or toxins) out of normal tissues. Uptake (SLC
family) and efflux (ABC family) transporters interact dynamically to mediate
the accumulation and translocation of drugs or endogenous substrates into a
138 DRUG TRANSPORTERS IN DRUG DISPOSITION, DRUG INTERACTIONS