THE DYNAMICS OF DRUG ABSORPTION, DISTRIBUTION, ACTION, AND ELIMINATION: INTRODUCTION

PHARMACOKINETICS AND PHARMACODYNAMICS: THE DYNAMICS OF DRUG ABSORPTION, DISTRIBUTION, ACTION, AND ELIMINATION: INTRODUCTION Numerous factors in addition to a known pharmacological action in a specific tissue at a particular receptor contribute to successful drug therapy. When a drug enters the body, the body begins immediately to work on the drug: absorption, distribution, metabolism (biotransformation), and elimination. These are the processes of pharmacokinetics. The drug also acts on the body, an interaction to which the concept of a drug receptor is key, since the receptor is responsible for the selectivity of drug action and for the quantitative relationship between drug and effect. The mechanisms of drug action are the processes of pharmacodynamics. The time course of therapeutic drug action in the body can be understood in terms of pharmacokinetics and pharmacodynamics (Figure 1-1). I. PHARMACOKINETICS: THE DYNAMICS OF DRUG ABSORPTION, DISTRIBUTION, METABOLISM, AND ELIMINATION PHYSICOCHEMICAL FACTORS IN TRANSFER OF DRUGS ACROSS MEMBRANES The absorption, distribution, metabolism, and excretion of a drug all involve its passage across cell membranes. Mechanisms by which drugs cross membranes and the physicochemical properties of molecules and membranes that influence this transfer are critical to understanding the disposition of drugs in the human body. The characteristics of a drug that predict its movement and availability at sites of action are its molecular size and shape, degree of ionization, relative lipid solubility of its ionized and nonionized forms, and its binding to serum and tissue proteins. In most cases, a drug must traverse the plasma membranes of many cells to reach its site of action. Although barriers to drug movement may be a single layer of cells (intestinal epithelium) or several layers of cells and associated extracellular protein (skin), the plasma membrane represents the common barrier to drug distribution. Cell Membranes. The plasma membrane consists of a bilayer of amphipathic lipids with their hydrocarbon chains oriented inward to the center of the bilayer to form a continuous hydrophobic phase and their hydrophilic heads oriented outward. Individual lipid molecules in the bilayer vary according to the particular membrane and can move laterally and organize themselves with cholesterol (e.g., sphingolipids), endowing the membrane with fluidity, flexibility, organization, high electrical resistance, and relative impermeability to highly polar molecules. Membrane proteins embedded in the bilayer serve as receptors, ion channels, or transporters to transduce electrical or chemical signaling pathways and provide selective targets for drug actions. These proteins may be associated with caveolin and sequestered within caveolae, they may be excluded from caveolae, or they may be organized in signaling domains rich in cholesterol and sphingolipid not containing caveolin. Cell membranes are relatively permeable to water either by diffusion or by flow resulting from hydrostatic or osmotic differences across the membrane, and bulk flow of water can carry with it drug molecules. However, proteins with drug molecules bound to them are too large and polar for this type of transport to occur; thus, transmembrane movement generally is limited to unbound drug. Paracellular transport through intercellular gaps is sufficiently large that passage across most capillaries is limited by blood flow and not by other factors (see below). As described later, this type of transport is an important factor in filtration across glomerular membranes in the kidney. Important exceptions exist in such capillary diffusion, however, because "tight" intercellular junctions are present in specific tissues, and paracellular transport in them is limited. Capillaries of the central nervous system (CNS) and a variety of epithelial tissues have tight junctions (see below). Bulk flow of water can carry with it small water-soluble substances, but bulk-flow transport is limited when the molecular mass of the solute exceeds 100 to 200 daltons. Accordingly, most large lipophilic drugs must pass through the cell membrane itself. Passive Membrane Transport. Drugs cross membranes either by passive processes or by mechanisms involving the active participation of components of the membrane. In passive transport, the drug molecule usually penetrates by diffusion along a concentration gradient by virtue of its solubility in the lipid bilayer. Such transfer is directly proportional to the magnitude of the concentration gradient across the membrane, to the lipid-water partition coefficient of the drug, and to the membrane surface area exposed to the drug. The greater the partition coefficient, the higher is the concentration of drug in the membrane, and the faster is its diffusion. After a steady state is attained, the concentration of the unbound drug is the same on both sides of the membrane if the drug is a nonelectrolyte. For ionic compounds, the steady-state concentrations depend on the electrochemical gradient for the ion and on differences in pH across the membrane, which may influence the state of ionization of the molecule disparately on either side of the membrane. Weak Electrolytes and Influence of pH. Most drugs are weak acids or bases that are present in solution as both the nonionized and ionized species. The nonionized molecules usually are more lipid-soluble and can diffuse readily across the cell membrane. In contrast, the ionized molecules usually are unable to penetrate the lipid membrane because of their low lipid solubility. Therefore, the transmembrane distribution of a weak electrolyte is determined by its pKa and the pH gradient across the membrane. The pKa is the pH at which half the drug (weak electrolyte) is in its ionized form. To illustrate the effect of pH on distribution of drugs, the partitioning of a weak acid (pKa = 4.4) between plasma (pH = 7.4) and gastric juice (pH = 1.4) is depicted in Figure 1-2. It is assumed that the gastric mucosal membrane behaves as a simple lipid barrier that is permeable only to the lipid-soluble, nonionized form of the acid. The ratio of nonionized to ionized drug at each pH is readily calculated from the Henderson-Hasselbalch equation: (1-1) This equation relates the pH of the medium around the drug and the drug's acid dissociation constant (pKa) to the ratio of the protonated (HA or BH+) and unprotonated (A- or B) forms, where HA « A- + H+ (Ka =[A-][H+]/[HA]) describes the dissociation of an acid, and BH+ « B + H+ (Ka =[B][H+]/[BH+]) describes the dissociation of the pronated form of a base. Thus, in plasma, the ratio of nonionized to ionized drug is 1:1000; in gastric juice, the ratio is 1:0.001. These values are given in brackets in Figure 1-2. The total concentration ratio between the plasma and the gastric juice therefore would be 1000:1 if such a system came to a steady state. For a weak base with a pKa of 4.4, the ratio would be reversed, as would the thick horizontal arrows in Figure 1-2, which indicate the predominant species at each pH. Accordingly, at steady state, an acidic drug will accumulate on the more basic side of the membrane and a basic drug on the more acidic side¾a phenomenon termed ion trapping. These considerations have obvious implications for the absorption and excretion of drugs, as discussed more specifically below. The establishment of concentration gradients of weak electrolytes across membranes with a pH gradient is a physical process and does not require an active electrolyte transport system. All that is necessary is a membrane preferentially permeable to one form of the weak electrolyte and a pH gradient across the membrane. The establishment of the pH gradient, however, is an active process. Carrier-Mediated Membrane Transport. While passive diffusion through the bilayer is dominant in the disposition of most drugs, carrier-mediated mechanisms also play an important role. Active transport is characterized by a direct requirement for energy, movement against an electrochemical gradient, saturability, selectivity, and competitive inhibition by cotransported compounds. Na+,K+-ATPase is an active transport mechanism. Secondary active transport uses the electrochemical energy stored in a gradient to move another molecule against a concentration gradient; e.g., the Na+-Ca2+exchange protein uses the energy stored in the Na+ gradient established by the Na+,K+-ATPase to export cytosolic Ca2+and maintain it at a low basal level, approximately 100 nM in most cells (see Chapter 33); similarly, the Na+-dependent glucose transporters SGLT1 and SGLT2 move glucose across membranes of gastrointestinal (GI) epithelium and renal tubules by coupling glucose transport to downhill Na+ flux. Facilitated diffusion describes a carrier-mediated transport process in which there is no input of energy, and therefore, enhanced movement of the involved substance is down an electrochemical gradient as in the permeation of glucose across a muscle cell membrane mediated by the insulin-sensitive glucose transporter protein GLUT4. Such mechanisms, which may be highly selective for a specific conformational structure of a drug, are involved in the transport of endogenous compounds whose rate of transport by passive diffusion otherwise would be too slow. In other cases, they function as a barrier system to protect cells from potentially toxic substances. Pharmacologically important transporters may mediate either drug uptake or efflux and often facilitate vectorial transport across polarized cells. An important efflux transporter present at many sites is the P-glycoprotein encoded by the multidrug resistance-1 (MDR1) gene. P-glycoprotein localized in the enterocyte limits the oral absorption of transported drugs because it exports compounds back into the GI tract subsequent to their absorption by passive diffusion. The P-glycoprotein also can confer resistance to some cancer chemotherapeutic agents (see Chapter 51). The importance of P-glycoprotein in the elimination of drugs is underscored by the presence of genetic polymorphisms in MDR1 (see Chapters 2 and 4 and Marzolini et al., 2004) that can affect therapeutic drug levels. Transporters and their roles in drug action are presented in detail in Chapter 2. DRUG ABSORPTION, BIOAVAILABILITY, AND ROUTES OF ADMINISTRATION Absorption is the movement of a drug from its site of administration into the central compartment (Figure 1-1) and the extent to which this occurs. For solid dosage forms, absorption first requires dissolution of the tablet or capsule, thus liberating the drug. The clinician is concerned primarily with bioavailability rather than absorption. Bioavailability is a term used to indicate the fractional extent to which a dose of drug reaches its site of action or a biological fluid from which the drug has access to its site of action. For example, a drug given orally must be absorbed first from the stomach and intestine, but this may be limited by the characteristics of the dosage form and the drug's physicochemical properties. In addition, drug then passes through the liver, where metabolism and biliary excretion may occur before the drug enters the systemic circulation. Accordingly, a fraction of the administered and absorbed dose of drug will be inactivated or diverted before it can reach the general circulation and be distributed to its sites of action. If the metabolic or excretory capacity of the liver for the drug is large, bioavailability will be reduced substantially (the first-pass effect). This decrease in availability is a function of the anatomical site from which absorption takes place; other anatomical, physiological, and pathological factors can influence bioavailability (see below), and the choice of the route of drug administration must be based on an understanding of these conditions.