NY, USA
1.1 INTRODUCTION
Since the discovery of transporter‐mediated drug transport, and the subsequent cloning and functional characterization of the individual transporter, our understanding of the roles of drug transporters play in human physiology, diseases, and drug therapy has exploded. Information about any of the many diverse aspects of drug transporters is scattered very widely, from journals of microbiology to those of pharmacology and genetics. Furthermore, many different, often conflicting, explanations given for these transporters need to be reconciled and rationalized. With such a need, comes this book Drug Transporters. This book, now in its 3rd edition, compiles and synthesizes the diverse body of knowledge on currently known drug transporters. This chapter provides an overview on the basic concepts/properties of drug transporters to serve as a foundation, allowing readers the opportunity to become familiar with those notions prior to reading the following chapters in the entire book.
1.2 WHAT ARE DRUG TRANSPORTERS?
Transporters are membrane proteins whose primary function is to facilitate the flux of molecules into and out of cells. Drug transporters did not evolve to transport specific drugs. Instead, their primary functions are to transport nutrients or endogenous substrates, such as sugars, amino acids, nucleotides, and vitamins, or to protect the body from dietary and environmental toxins. However, the specificity of these transporters is not strictly restricted to their physiological substrates. Drugs that bear significant structural similarity to the physiological substrates have the potential to be recognized and transported by these transporters. As a consequence, these transporters also play significant roles in determining the bioavailability, therapeutic efficacy, and pharmacokinetics of a variety of drugs. Nevertheless, because drugs may compete with the physiological substrates of these transporters, they are also likely to interfere with the transport of endogenous substrates and consequently produce deleterious effects on body homeostasis.
1.3 STRUCTURE AND MODEL OF DRUG TRANSPORTERS
Because of the involvement of transporters in all facets of drug absorption, tissue distribution, excretion, and efficacy/toxicity, characterization of transporter structure can provide a scientific basis for understanding drug delivery and disposition, as well as the molecular mechanisms of drug interaction and inter‐individual/inter‐species differences. However, compared to soluble proteins, the atomic resolution crystal structures of membrane transporters have been extremely difficult to obtain for several reasons: first is the amphipathic nature of the surface of the transporters, with a hydrophobic area in contact with membrane phospholipids and polar surface areas in contact with the aqueous phases on both sides of the membrane; second is the low abundance of many transporters in the membrane, making it impossible to overexpress them, a prerequisite for structural studies; and third is the inherent conformational flexibility of the transporters, making it difficult to obtain stable crystals.
Due to these difficulties, high‐resolution three‐dimensional structures have been obtained for only limited number of transporters. For other transporters, the three‐dimensional structures have been achieved through homology modeling. In this approach, similar folding patterns between any protein and one for which the crystal structure is known enable the construction of a fairly accurate three‐dimensional protein model of the unknown structure using the related crystal structure as a template and modern computational techniques. Three‐dimensional structures have revealed that transporters have alpha‐helical structures of the membrane‐spanning domains, and some of the helices have irregular shapes with kinks and bends. Certain transporters undergo substantial movements during the substrate translocation process. Recent advances in cryo‐electron microscopy (cryo‐EM) have allowed high‐resolution determination of the structure of macromolecules without the need for crystallization and therefore viewed as an alternative to X‐ray crystallography. Construction of three‐dimensional transporter models have provided insight into functional mechanisms and molecular structures and enabled formulation of new hypotheses regarding transporter structure and function, which may be experimentally validated.
1.4 TRANSPORT MECHANISMS
Not only different transporters reside in the membrane with different three‐dimensional structures but also they transport their substrates through different transport mechanisms. According to their transport mechanisms, transporters can be divided into passive and active transporters: passive transporters, also called facilitated transporters, allow molecules to move across cell membranes down their electrochemical gradients. Such a spontaneous process decreases free energy and increases entropy in a system, and therefore does not consume any chemical energy. In contrast to facilitated transporters, active transporters typically move molecules against their electrochemical gradients; such process is entropically unfavorable and therefore needs the coupling of the hydrolysis of ATP as an energy source. This coupling can be either primary or secondary. In primary active transport, transporters that move molecules against their electrical/chemical gradient hydrolyze ATP. In the secondary active transport, transporters utilize ion gradients, such as sodium or proton gradients, across the membrane produced by the primary active transporters and transport substrates against an electrochemical difference.
1.5 POLARIZED EXPRESSION OF DRUG TRANSPORTERS IN BARRIER EPITHELIUM
Most drug transporters are expressed in tissues with barrier functions such as the liver, kidney, intestine, placenta, and brain. Cells at the border of these barriers are usually polarized. For example, enterocytes of intestine and proximal tubule cells of kidney have an apical domain facing the lumen and a basolateral domain facing the blood circulation; hepatocytes polarize into a canalicular membrane facing the bile duct and sinusoidal membrane facing the blood circulation; syncytiotrophoblasts of placenta have an apical domain facing maternal blood and a basolateral domain facing the fetus. Brain capillary endothelial cells, which function as the blood–brain barrier, also polarize into apical and basolateral membranes. In most cases, the expression of drug transporters is highly restricted to one side (i.e., apical or basolateral domain) of polarized cells. Such polarized expression of the transporters is essential for the concerted transport of drugs in the same direction. One of the most well‐studied examples of concerted transport is the kidney. Kidney proximal tubule cells play a critical role in the body clearance of drugs. These drugs are first taken up from the blood into the proximal tubule cells by transporters at the basolateral membrane. Once inside the cells, these drugs are then transported out of the cells into the tubule lumen by transporters at the apical membrane and subsequently eliminated in the urine. The alliance between transporters at both the basolateral membrane and the apical membrane of the kidney proximal tubule cells ensures the clearance of the drugs from the body.
1.6 CLASSIFICATIONS OF DRUG TRANSPORTERS
Drug transporters can be classified in a number of different manners, including as efflux transporters versus influx transporters, secretory transporters versus absorptive transporters, and ABC transporters versus SLC transporters.
1.6.1 Definition of Efflux and Influx Transporters
Drug transporters can be categorized as efflux or influx transporters according to the direction they transport substrate across the cell membranes. This classification is often observed in the literature where drug transport studies are performed at the cellular level. With this definition, transporters that pump the substrates out of the cells are called efflux transporters, whereas transporters that transfer substrates into cells are called influx transporters.
1.6.2 Definition of Absorptive and Secretory Transporters
The other way of classifying drug transporters is from a pharmacodynamic or pharmacokinetic
