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Transporters are membrane proteins that are present in all organisms. These proteins control the influx of essential nutrients and ions and the efflux of cellular waste, environmental toxins, drugs, and other xenobiotics. Consistent with their critical roles in cellular homeostasis, ∼2000 genes in the human genome, ∼7% of the total number of genes, code for transporters or transporter-related proteins. The functions of membrane transporters may be facilitated (equilibrative, not requiring energy) or active (requiring energy). In considering the transport of drugs, pharmacologists generally focus on transporters from two major superfamilies, ABC (ATP binding cassette) and SLC (solute carrier) transporters.

Most ABC proteins are primary active transporters, which rely on ATP hydrolysis to actively pump their substrates across membranes. There are 49 known genes for ABC proteins that can be grouped into seven subclasses or families (ABCA to ABCG) (Borst and Elferink, 2002). Among the best recognized transporters in the ABC superfamily are P-glycoprotein (P-gp, encoded by ABCB1, also termed MDR1) and the cystic fibrosis transmembrane regulator (CFTR, encoded by ABCC7).

The SLC superfamily includes genes that encode facilitated transporters and ion-coupled secondary active transporters that reside in various cell membranes. Forty-eight SLC families with ∼315 transporters have been identified in the human genome (Hediger, 2004). Many serve as drug targets or in drug absorption and disposition. Widely recognized SLC transporters include the serotonin (5-HT) and dopamine transporters (SERT, encoded by SLC6A4; DAT, encoded by SLC6A3).

Analysis of physical chemical evidence suggests that the involvement of transporters in the passage of drugs across biological membranes may be more the rule than the exception (Dobson and Kell, 2008). Drug-transporting proteins operate in pharmacokinetic and pharmacodynamic pathways, including pathways involved in both therapeutic and adverse effects (Figure 5–1).

Figure 5–1.

Roles of membrane transporters in pharmacokinetic pathways. Membrane transporters (T) play roles in pharmacokinetic pathways (drug absorption, distribution, metabolism, and excretion), thereby setting systemic drug levels. Drug levels often drive therapeutic and adverse drug effects.


Pharmacokinetics. Transporters that are important in pharmacokinetics generally are located in intestinal, renal, and hepatic epithelia, where they function in the selective absorption and elimination of endogenous substances and xenobiotics, including drugs (Ciarimboli, 2008; El-Sheikh et al., 2008; Shitara et al., 2005; Srimaroeng et al., 2008). Transporters work in concert with drug-metabolizing enzymes to eliminate drugs and their metabolites (Figure 5–2). In addition, transporters in various cell types mediate tissue-specific drug distribution (drug targeting). Conversely, transporters also may serve as protective barriers to particular organs and cell types. Access of solutes to several tissues such as the brain and testes is restricted by a ...

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