The Biology and Function of Transporters

J-M Scherrmann, University of Paris, Paris, France © 2007 Elsevier Ltd. All Rights Reserved.

5.04.1 Introduction 51

5.04.2 Membrane Transport Proteins in Biological Systems 52

5.04.2.1 Passive and Active Permeation 52

5.04.2.2 Transport Modes 52

5.04.3 Biology of Membrane Transport Proteins 54

5.04.3.1 Genes and Classification 54

5.04.3.2 Basic Structure 55

5.04.3.3 Transport Kinetics 55

5.04.4 Transporters in Drug Disposition 56

5.04.4.1 Adenosine Triphosphate-Binding Cassette Transporter Superfamily 57

5.04.4.1.1 ABCB subfamily 58

5.04.4.1.2 ABCC subfamily 60

5.04.4.1.3 ABCG subfamily 62

5.04.4.2 Solute Carrier Transporter Superfamily 64

5.04.4.2.1 OATP (SLC21/SLCO) transporters 64

5.04.4.2.2 OCT (SLC22) transporters 68

5.04.4.2.3 OAT (SLC22) transporters 70

5.04.4.2.4 PEPT1 (SLC15A1) and PEPT2 (SLC15A2) transporters 71

5.04.4.2.5 CNT (SLC28) and ENT (SLC29) transporters 72

5.04.5 Expression and Function Properties of Transporters in Tissues 73

5.04.5.1 Transporters at the Plasma Membrane and Within Cells 73

5.04.5.2 Tissue Specificity 73

5.04.5.3 Polarized Cellular Distribution 73

5.04.5.4 Coordinated and Vectorial Transports 74

5.04.5.5 Coordination between Transporters and Enzymes 74

5.04.5.6 Polyspecific Transport and Inhibition 74

5.04.5.7 Variations in Transport Kinetics 74

5.04.6 Roles of Transporters in Pharmacokinetics 75

5.04.6.1 Intestinal Absorption 75

5.04.6.2 Liver and Hepatic Clearance 77

5.04.6.3 Blood Barriers and Tissue Distribution 78

5.04.6.4 Kidney and Renal Clearance 79

5.04.6.5 Transporters and the Biopharmaceutics Classification System 81

5.04.7 Conclusion 82 References 82

Pharmacokinetics has been defined over the past several decades as the study of drug absorption, distribution, metabolism, and excretion (ADME) when the drug is introduced into a biological system such as the human body. Most of the molecular processes responsible for the fate of a drug in the body were attributed to the passive crossing of the bilayer cell membranes. These explained a large part of how a drug was believed to be absorbed, distributed, and

5.04.1 Introduction

Pharmacokinetics has been defined over the past several decades as the study of drug absorption, distribution, metabolism, and excretion (ADME) when the drug is introduced into a biological system such as the human body. Most of the molecular processes responsible for the fate of a drug in the body were attributed to the passive crossing of the bilayer cell membranes. These explained a large part of how a drug was believed to be absorbed, distributed, and eliminated. Several drug descriptors, such as molecular weight, degree of ionization, and solubility, were used to explain how a drug crossed biological membranes. Other pharmacokinetic effectors were considered, such as the metabolizing enzymes, that played an important role in drug biotransformation and the circulating plasma proteins defining the so-called 'fraction of free drug' available for tissue distribution. Elimination was also defined as the endpoint of all pharmacokinetic events, by which the more hydrophilic drugs or their metabolites were excreted in urine or bile.

Pharmacokineticists learned quite early that the overall renal clearance of a drug results from a combination of three processes: glomerular filtration, tubular secretion, and reabsorption. These last two processes have long been known to be mediated by carrier systems. In these systems, membrane proteins transport solutes in oriented directions. It was gradually realized that drugs could cross biological membranes by these carrier-mediated processes as well as by passive diffusion. This view of pharmacokinetics is now challenged by the growing importance of transporters, a relatively new and potentially major contributor. The impact of drug transporters on pharmacokinetics has suffered from the fact that less is known about them than about drug-metabolizing enzymes. Schwenk1 published a review in 1987 that stated that ''drug transport in the intestine occurs mainly by diffusion and the contribution of intestinal drug carriers seems to be of minor importance.'' He also pointed that ''the liver is the organ where carrier-mediated drugs predominate'' and that there may be four hypothetical carrier systems, called ''carrier 1, 2, 3 and 4,'' for drug uptake by hepatic cells. At the same time, the main enzymes implicated in drug metabolism were identified and the factors causing variations, such as the regulation and genetic polymorphism of these enzymes, were extensively studied. We are now in a position to complete the list of drug transporters, the tissues in which they occur and function, how they are regulated, and the clinical relevance of their presence in normal and diseased tissues. Nevertheless, despite the tremendous efforts that have been made in recent years, we still lack a significant amount of information about the fundamental contributions that transporters make to the pharmacokinetic processes that regulate the disposition of drugs in the body.

5.04.2 Membrane Transport Proteins in Biological Systems

5.04.2.1 Passive and Active Permeation

The exchange of solutes between body compartments depends to a considerable extent on the properties of the body that allow easy communication between tissues and compartments via pores and fenestra on the walls of the blood vessel or gap junctions between cells. These features allow free solutes to move in both directions through biological membranes by the so-called 'paracellular pathway.' But the organs of the body and pharmacological targets are not readily accessible to exogenous molecules because of the integrity of the lipid bilayer membranes that protect the interiors of cells. Some physiological barriers like the blood-brain barrier (BBB), the blood-placenta barrier, and the blood-testis barrier are so impermeable that solutes can only cross the lipid bilayer by a transcellular pathway. It has been established for some time that with advantageous gradient conditions only small nonpolar, uncharged molecules, such as oxygen, carbon dioxide, water, and ethanol, can diffuse easily through the membranes, whereas charged small ions, such as sodium and potassium, and large molecules, such as glucose (180 Da), are considerably less able to permeate than water (Figure 1). As the delivery of many polar molecules, such as anions and cations, vitamins, sugars, nucleosides, amino acids, peptides, bile acids, and porphyrins, to cells is essential for life, essential transporter proteins anchored in the lipid bilayer have evolved to permit their exchange between cells and their environment.

There are two principal classes of transport proteins: the proteins that form channels or pores, and the transporters. Channels are responsible for the facilitated diffusion of ions and small nutrient molecules down their electrochemical gradients. The flow of ions or solutes through channels is controlled by the opening of the channels via gating mechanisms and the single-channel conductance (number of charges per second at a given voltage). Some channels are more selective and have specific binding sites; they undergo changes of conformation and these changes regulate their opening to solute traffic.2 The second class of transporters or carriers undergoes a conformational change during the translocation of a solute across the membrane. Transporters that facilitate the movement of solutes into the cell are called influx (import) transporters, while those that remove substances from the cytosol of the cell are efflux (export) transporters.

5.04.2.2 Transport Modes

Influx and efflux transporters can be further classified on the basis of their energy requirements.3 Like protein channels, passive transporters, or facilitated transporters or uniporters, allow net solute flow down an electrochemical concentration gradient.

In contrast, active transport leads to the movement of solutes against an electrochemical gradient across the membrane. Active transport always occurs in a specific direction because it is coupled to an energy source. Several types of transporters have been identified; they differ by their energy source and the direction of transport (Figure 2). The

Gases and hydrophobic molecules

Polar and charged molecules

Low molecular weight Medium molecular weight

Glucose (180)

Ions

Figure 1 Permeation of ions and molecules through the membrane lipid bilayer. Small, lipophilic molecules with no charge are more likely to cross the membrane by passive diffusion. Ions and high molecular weight hydrophilic compounds cannot cross the lipid bilayer in the absence of pores, channels, or specific transporters.

Figure 1 Permeation of ions and molecules through the membrane lipid bilayer. Small, lipophilic molecules with no charge are more likely to cross the membrane by passive diffusion. Ions and high molecular weight hydrophilic compounds cannot cross the lipid bilayer in the absence of pores, channels, or specific transporters.

Active transport

Passive transport (facilitated diffusion)

Primary

Secondary

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