Chapter 4 Physiologic Factors Related to Drug Absorption PDF

Access Provided by: Shargel and Yu's Applied Biopharmaceutics and Pharmacokinetics, 8e Chapter 4: Physiologic Factors Related to Drug Absorption Phillip M....

Access Provided by: Shargel and Yu's Applied Biopharmaceutics and Pharmacokinetics, 8e Chapter 4: Physiologic Factors Related to Drug Absorption Phillip M. Gerk CHAPTER OBJECTIVES Define passive and active drug absorption. Explain how Fick’s law of diffusion relates to passive drug absorption. Calculate the percent of drug nonionized and ionized for a weak acid or weak­base drug using the Henderson–Hasselbalch equation and explain how this may affect drug absorption. Define transcellular and paracellular drug absorption and explain using drug examples. Describe the anatomy and physiology of the GI tract and explain how stomach emptying time and GI transit time can alter the rate and extent of drug absorption. Explain the effect of food on GI physiology and systemic drug absorption. Describe the various transporters and how they influence the pharmacokinetics of drug disposition in the GI tract. Explain the pH­partition hypothesis and how gastrointestinal pH and the pKa of a drug may influence systemic drug absorption. Describe how drug absorption may be affected by a disease that causes changes in intestinal blood flow and/or motility. List the major factors that affect drug absorption from oral and non­oral routes of drug administration. Describe various methods that may be used to study oral drug absorption from the GI transit. DRUG ABSORPTION AND DESIGN OF A DRUG PRODUCT Major considerations in the design of a drug product include the therapeutic objective, the application site, and systemic drug absorption from the application site. If the drug is intended for systemic activity, the drug should ideally be completely and consistently absorbed from the application site. In contrast, if the drug is intended for local activity, then systemic absorption from the application should be minimal to prevent systemic drug exposure and possible systemic side effects. For extended­release drug products, the drug product should remain at or near the application site and then slowly release the drug for the desired period of time. The systemic absorption of a drug is dependent on (1) the physicochemical properties of the drug, (2) the nature of the drug product, and (3) the anatomy and physiology of the drug absorption site. Thus, the rate and extent to which a drug gets from the site of administration to the blood will depend on its release from the dosage form into physiologic fluids, the permeability of the drug through the tissues in the absorption site, and any degradation or metabolism of the drug that may occur before reaching the blood. In order to develop a drug product that elicits the desired therapeutic objective, the pharmaceutical scientist must have a thorough understanding of the biopharmaceutic properties of the drug and drug product and the physiologic and pathologic factors affecting drug absorption from the application site. A general description of drug absorption, distribution, and elimination is shown in Fig. 4­1. Pharmacists must also understand the relationship of drug dosage to therapeutic efficacy and adverse reactions and the potential for drug–drug and drug–nutrient interactions. This chapter will focus on the anatomic and physiologic considerations for the systemic absorption of a drug, whereas Chapters 7 to 8 will focus on the biopharmaceutic aspects of the drug and drug­product design, including considerations in manufacturing and performance tests. Since the major route of drug administration is the oral route, major emphasis in this chapter will be on gastrointestinal (GI) drug absorption. Downloaded FIGURE 4­1 2024­9­11 12:33 A Your IP is 49.151.13.23 Chapter 4: Physiologic Factors Related to Drug Absorption, Phillip M. Gerk Page 1 / 51 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility The interrelationship of the absorption, distribution, binding, metabolism, and excretion of a drug and its concentration at its sites of action. (Reproduced with permission from Brunton LL, Hilal­Dandan R, Knollmann BC: Goodman & Gilman’s Pharmacological Basis of Therapeutics, 13th ed. New York, NY: McGraw Hill; 2018.) application site. A general description of drug absorption, distribution, and elimination is shown in Fig. 4­1. Pharmacists must also understand the relationship of drug dosage to therapeutic efficacy and adverse reactions and the potential for drug–drug and drug–nutrient interactions. This chapter will focus on the anatomic and physiologic considerations for the systemic absorption of a drug, whereas Chapters 7 to 8 will focus on the biopharmaceutic aspects of the drug and drug­product design, including considerations in manufacturing and performance tests. Since the major Access Provided by: route of drug administration is the oral route, major emphasis in this chapter will be on gastrointestinal (GI) drug absorption. FIGURE 4­1 The interrelationship of the absorption, distribution, binding, metabolism, and excretion of a drug and its concentration at its sites of action. (Reproduced with permission from Brunton LL, Hilal­Dandan R, Knollmann BC: Goodman & Gilman’s Pharmacological Basis of Therapeutics, 13th ed. New York, NY: McGraw Hill; 2018.) ROUTE OF DRUG ADMINISTRATION Drugs may be given by parenteral, enteral, inhalation, intranasal, transdermal (percutaneous), or intranasal route for systemic absorption. Each route of drug administration has certain advantages and disadvantages. Characteristics of the more common routes of drug administration are listed in Table 4­1. The systemic availability and onset of drug action are affected by blood flow at the administration site, the physicochemical characteristics of the drug and the drug product, and any pathophysiologic condition at the absorption site. After a drug is systemically absorbed, drug distribution and clearance follow normal physiological conditions of the body. Drug distribution and clearance are not usually altered by the drug formulation but may be altered by pathology, genetic polymorphism, and drug–drug interactions, as discussed in other chapters. TABLE 4­1 Common Routes of Drug Administration Route Bioavailability Advantages Disadvantages Parenteral Routes Intravenous Complete (100%) Drug is given for immediate effect. Increased chance for adverse reaction. bolus (IV) systemic drug Possible anaphylaxis. absorption. Instant bioavailability. Intravenous Complete (100%) Plasma drug levels more precisely controlled. Requires skill in insertion of infusion set. infusion (IV inf) systemic drug May inject large fluid volumes. Tissue damage at site of injection absorption. May use drugs with poor lipid solubility and/or irritating drugs. (infiltration, necrosis, or sterile abscess). Rate of drug absorption controlled by infusion rate. Subcutaneous Prompt from Generally, used for insulin injection. Rate of drug absorption depends on blood Downloaded 2024­9­11aqueous (SC) injection 12:33 solution. A Your IP is 49.151.13.23 flow and injection volume. Chapter 4: Physiologic Factors Related to Drug Absorption, Phillip M. Gerk Page 2 / 51 Slow absorption from Insulin formulation can vary from short to ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility repository intermediate and long acting. formulations.  Rate of drug absorption controlled by Access Provided by: infusion rate. Subcutaneous Prompt from Generally, used for insulin injection. Rate of drug absorption depends on blood (SC) injection aqueous solution. flow and injection volume. Slow absorption from Insulin formulation can vary from short to repository intermediate and long acting. formulations. Intradermal Drug injected into Often used for allergy and other diagnostic tests, such as Some discomfort at site of injection. injection surface area (dermal) tuberculosis. of skin. Intramuscular Rapid from aqueous Easier to inject than IV injection. Irritating drugs may be very painful. (IM) injection solution. Larger volumes may be used compared to SC solutions. Different rates of absorption depending on Slow absorption from muscle group injected and blood flow. nonaqueous (oil) solutions. Intra­arterial 100% of solution is Used in chemotherapy to target drug to organ. Drug may also distribute to other tissues injection absorbed. and organs in the body. Intrathecal 100% of solution is Drug is directly injected into cerebrospinal fluid (CSF) for uptake Careful injection skill required. injection absorbed. into brain. Intraperitoneal In laboratory animals Used more in small laboratory animals. Less common injection Drug absorption via mesenteric veins to injection (eg, rat) drug in humans. Used for renally impaired patients on peritoneal liver, may have some hepatic clearance absorption dialysis who develop peritonitis. prior to systemic absorption. resembles oral absorption. Enteral Routes Buccal or Rapid absorption No “first­pass” effects. Buccal route may be formulated for local Some drugs may be swallowed. Not for sublingual (SL) from lipid soluble prolonged action, eg, adhere to the buccal mucosa with some most drugs or drugs with high doses. drugs. antifungal. Buccal is different from SL, which is usually placed under tongue. Oral (PO) Absorption may vary. Safest and easiest route of drug administration. Some drugs may have erratic absorption, Generally, slower May use immediate­release and modified­release drug be unstable in the gastrointestinal tract, or absorption rate products. be metabolized by liver prior to systemic compared to IV bolus absorption. or IM injection. Rectal (PR) Absorption may vary Useful when patient cannot swallow medication. Absorption may be erratic. from suppository. Used for local and systemic effects. Suppository may migrate to different More reliable position. absorption from Some patient discomfort. enema (solution). Other Routes Transdermal Slow absorption, rate Transdermal delivery system (patch) is easy to use. Some irritation by patch or drug. may vary. Used for lipid­soluble drugs with low dose and low molecular Permeability of skin variable with Downloaded 2024­9­11Increased 12:33 Aabsorption weight (MW). Your IP is 49.151.13.23 condition, anatomic site, age, and gender. Chapter 4: Physiologicwith Factors Related to Drug Absorption, Phillip M. Gerk occlusive Page 3 / 51 Type of cream or ointment base affects ©2024 McGraw Hill. Alldressing. Rights Reserved. Terms of Use Privacy Policy Notice Accessibility drug release and absorption. Inhalation and Rapid absorption. May be used for local or systemic effects. Particle size of drug determines anatomic  Other Routes Access Provided by: Transdermal Slow absorption, rate Transdermal delivery system (patch) is easy to use. Some irritation by patch or drug. may vary. Used for lipid­soluble drugs with low dose and low molecular Permeability of skin variable with Increased absorption weight (MW). condition, anatomic site, age, and gender. with occlusive Type of cream or ointment base affects dressing. drug release and absorption. Inhalation and Rapid absorption. May be used for local or systemic effects. Particle size of drug determines anatomic intranasal Total dose absorbed placement in respiratory tract. is variable. May stimulate cough reflex. Some drug may be swallowed. Many drugs are not administered orally because of insufficient systemic absorption from the GI tract. The diminished oral drug absorption may be due to drug instability in the GI tract, drug degradation by the digestive enzymes in the intestine, high hepatic clearance (first­pass effect), and efflux transporters such as P­glycoprotein resulting in poor and/or erratic systemic drug availability. Some orally administered drugs, such as cholestyramine and others (Table 4­2), are not intended for systemic absorption but may be given orally for local activity in the GI tract. However, some oral drugs such as mesalamine and balsalazide that are intended for local activity in the GI tract may also have a significant amount of systemic drug absorption. Small, highly lipid­soluble drugs such as nitroglycerin and fentanyl that are subject to high first­pass effects if swallowed may be given by buccal or sublingual routes to bypass degradation in the GI tract and/or first­pass effects. Insulin is an example of protein peptide drug generally not given orally due to degradation and inadequate absorption in the GI tract. TABLE 4­2 Drugs Given Orally for Local Drug Activity in the Gastrointestinal Tract Drug Example Comment Cholestyramine Questran Cholestyramine resin is the chloride salt of a basic anion exchange resin, a cholesterol­lowering agent. Cholestyramine resin is hydrophilic but insoluble in water and not absorbed from the digestive tract. Balsalazide Colazal Balsalazide disodium is a prodrug that is enzymatically cleaved in the colon to produce mesalamine, an anti­inflammatory disodium drug. Balsalazide disodium is intended for local action in the treatment of mildly to moderately active ulcerative colitis. Balsalazide disodium and its metabolites are absorbed from the lower intestinal tract and colon. Mesalaminea Asacol Asacol HD delayed­release tablets have an outer protective coat and an inner coat, which dissolves at pH 7 or greater, delayed­release HD tablet releasing mesalamine in the terminal ileum for topical anti­inflammatory action in the colon. tablet Mesalamine Pentasa Pentasa capsule is an ethylcellulose­coated, controlled­release capsule formulation of mesalamine designed to release controlled­ capsule therapeutic quantities of mesalamine throughout the gastrointestinal tract. release capsule aAlso referred to as 5­aminosalicylic acid or 5­ASA. Although mesalamine is indicated for local anti­inflammatory activity in the lower GI tract, mesalamine is systemically absorbed from the GI tract. Biotechnology­derived drugs (see Chapter 10) are usually given by the parenteral route because they are too labile in the GI tract to be administered orally. For example, erythropoietin and human growth hormone (somatropin) are administered intramuscularly, and insulin is given subcutaneously or intramuscularly. Subcutaneous injection results in relatively slow absorption from the site of administration compared to intravenous injection, which provides immediate delivery to the plasma. Pathophysiologic conditions such as burns will increase the permeability of drugs across the skin compared with normal intact skin. Currently, pharmaceutical research is being directed to devise approaches for the oral absorption of various protein drugs such as insulin (Dhawan et al, 2009). Recently, inhaled insulin was approved for use by the FDA but the product was discontinued by the manufacturer because of poor patient and physician acceptance of this new route of administration. Biotechnology­derived drugs are discussed more fully in Chapter Downloaded 10. 2024­9­11 12:33 A Your IP is 49.151.13.23 Chapter 4: Physiologic Factors Related to Drug Absorption, Phillip M. Gerk Page 4 / 51 When ©2024a McGraw drug is administered by Reserved. Hill. All Rights an extravascular Termsroute of administration of Use (eg, Privacy Policy oral, topical, Notice intranasal, inhalation, rectal), the drug must first be Accessibility absorbed into the systemic circulation and then diffuse or be transported to the site of action before eliciting biological and therapeutic activity. The general principles and kinetics of absorption from these extravascular sites follow the same principles as oral dosing, although the physiology of the or intramuscularly. Subcutaneous injection results in relatively slow absorption from the site of administration compared to intravenous injection, which provides immediate delivery to the plasma. Pathophysiologic conditions such as burns will increase the permeability of drugs across the skin compared with normal intact skin. Currently, pharmaceutical research is being directed to devise approaches for the oral absorption of various protein drugs such as insulin (Dhawan et al, 2009). Recently, inhaled insulin was approved for use by the FDA but the product was discontinued byAccess the Provided by: manufacturer because of poor patient and physician acceptance of this new route of administration. Biotechnology­derived drugs are discussed more fully in Chapter 10. When a drug is administered by an extravascular route of administration (eg, oral, topical, intranasal, inhalation, rectal), the drug must first be absorbed into the systemic circulation and then diffuse or be transported to the site of action before eliciting biological and therapeutic activity. The general principles and kinetics of absorption from these extravascular sites follow the same principles as oral dosing, although the physiology of the site of administration differs. NATURE OF CELL MEMBRANES Many drugs administered by extravascular routes are intended for local effect. Other drugs are designed to be absorbed from the site of administration into the systemic circulation. For systemic drug absorption, the drug may cross cellular membranes. After oral administration, drug molecules must cross the intestinal epithelium by going either through or between the epithelial cells to reach the systemic circulation. The permeability of a drug at the absorption site into the systemic circulation is intimately related to the molecular structure and properties of the drug and to the physical and biochemical properties of the cell membranes. Once in the plasma, the drug may act directly or may have to cross biological membranes to reach the site of action. Therefore, biological membranes potentially pose a significant barrier to drug delivery. Transcellular absorption is the process of drug movement across a cell. Some polar molecules may not be able to traverse the cell membrane but instead go through gaps or tight junctions between cells, a process known as paracellular drug diffusion. Figure 4­2 shows the difference between the two processes. Some drugs are probably absorbed by a mixed mechanism involving multiple processes. FIGURE 4­2 Summary of intestinal epithelial transporters. Transporters shown by square and oval shapes demonstrate active and facilitated transporters, respectively. Names of cloned transporters are shown with square or oval shapes. In the case of active transporters, arrows in the same direction represent symport of substance and the driving force. Arrows going in the reverse direction mean the antiport. (Reproduced with permission from Tsuji A, Tamai I. Carrier­mediated intestinal transport of drugs, Pharm Res 1996 Jul;13(7):963­977.) Note that BCRP and MRP2 are positioned similarly to MDR1 (P­glycoprotein). Downloaded 2024­9­11 12:33 A Your IP is 49.151.13.23 Chapter 4: Physiologic Factors Related to Drug Absorption, Phillip M. Gerk Page 5 / 51 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility respectively. Names of cloned transporters are shown with square or oval shapes. In the case of active transporters, arrows in the same direction represent symport of substance and the driving force. Arrows going in the reverse direction mean the antiport. (Reproduced with permission from Tsuji A, Tamai I. Carrier­mediated intestinal transport of drugs, Pharm Res 1996 Jul;13(7):963­977.) Note that BCRP and MRP2 are positioned similarly Access Provided by: to MDR1 (P­glycoprotein). Membranes are major structures in cells, surrounding the entire cell (plasma membrane) and acting as a boundary between the cell and the interstitial fluid. In addition, membranes enclose most of the cell organelles (eg, the mitochondrion membrane). Functionally, cell membranes are semipermeable partitions that act as selective barriers to the passage of molecules. Water, some selected small molecules, and lipid­soluble molecules pass readily through such membranes, whereas highly charged molecules and large molecules, such as proteins and protein­bound drugs, do not. The transmembrane movement of drugs is influenced by the composition and structure of the plasma membranes. Cell membranes are generally thin, approximately 70–100 Å in thickness. Cell membranes are composed primarily of phospholipids in the form of a bilayer interdispersed with carbohydrates and protein groups. There are several theories as to the structure of the cell membrane. The lipid bilayer or unit membrane theory, originally proposed by Davson and Danielli (1952), considers the plasma membrane to be composed of two layers of phospholipid between two surface layers of proteins, with the hydrophilic “head” groups of the phospholipids facing the protein layers and the hydrophobic “tail” groups of the phospholipids aligned in the interior. The lipid bilayer theory explains the observation that lipid­soluble drugs tend to penetrate cell membranes more easily than polar molecules. However, the bilayer cell membrane structure does not account for the diffusion of water, small­molecular­weight molecules such as urea, and certain charged ions. The fluid mosaic model, proposed by Singer and Nicolson (1972), explains the transcellular diffusion of polar molecules (Lodish, 1979). According to Downloaded 2024­9­11 this model, the 12:33 consists cell membrane A Your ofIPglobular is 49.151.13.23 proteins embedded in a dynamic fluid, lipid bilayer matrix (Fig. 4­3). These proteins provide a Chapter 4: Physiologic Factors Related to Drug Absorption, Phillip M. Gerk Page 6 / 51 pathway for the selective transfer of certain polar molecules and charged ions through the lipid barrier. As shown in Fig. 4­3, transmembrane proteins ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility are interdispersed throughout the membrane. Two types of pores of about 10 nm and 50–70 nm were inferred to be present in membranes based on capillary membrane transport studies (Pratt and Taylor, 1990). These small pores provide a channel through which water, ions, and dissolved solutes surface layers of proteins, with the hydrophilic “head” groups of the phospholipids facing the protein layers and the hydrophobic “tail” groups of the phospholipids aligned in the interior. The lipid bilayer theory explains the observation that lipid­soluble drugs tend to penetrate cell membranes more easily than polar molecules. However, the bilayer cell membrane structure does not account for the diffusion of water, small­molecular­weight Access Provided by: molecules such as urea, and certain charged ions. The fluid mosaic model, proposed by Singer and Nicolson (1972), explains the transcellular diffusion of polar molecules (Lodish, 1979). According to this model, the cell membrane consists of globular proteins embedded in a dynamic fluid, lipid bilayer matrix (Fig. 4­3). These proteins provide a pathway for the selective transfer of certain polar molecules and charged ions through the lipid barrier. As shown in Fig. 4­3, transmembrane proteins are interdispersed throughout the membrane. Two types of pores of about 10 nm and 50–70 nm were inferred to be present in membranes based on capillary membrane transport studies (Pratt and Taylor, 1990). These small pores provide a channel through which water, ions, and dissolved solutes such as urea may move across the membrane. FIGURE 4­3 Model of the plasma membrane including proteins and carbohydrates as well as lipids. Integral proteins are embedded in the lipid bilayer; peripheral proteins are merely associated with the membrane surface. The carbohydrate consists of monosaccharides, or simple sugars, strung together in chains attached to proteins (forming glycoproteins) or to lipids (forming glycolipids). The asymmetry of the membrane is manifested in several ways. Carbohydrates are always on the exterior surface and peripheral proteins are almost always on the cytoplasmic, or inner, surface. The two lipid monolayers include different proportions of the various kinds of lipid molecules. Most important, each species of integral protein has a definite orientation, which is the same for every molecule of that species. (© George V. Kelvin.) Membrane proteins embedded in the bilayer serve special purposes. These membrane proteins function as structural anchors, receptors, ion channels, or transporters to transduce electrical or chemical signaling pathways that facilitate or prevent selective actions. In contrast to simple bilayer structure, membranes are highly ordered and compartmented (Brunton, 2011). Indeed, many early experiments on drug absorption or permeability using isolated gut studies were proven not valid because the membrane proteins and electrical properties of the membrane were compromised in many epithelial cell membranes, including those of the GI tract. PASSAGE OF DRUGS ACROSS CELL MEMBRANES There are several mechanisms by which drugs may pass through cell membranes. Passive (simple) diffusion does not involve any energy or transporter protein. Carrier­mediated transport involves a protein which facilitates the movement of the drug across the membrane, either with or without an energy source. Active transport is a special case of carrier­mediated transport, in which an energy source is used to drive the transport process. These different types of transport will each be discussed further in the following sections. Passive Diffusion Theoretically, a lipophilic drug may pass through the cell or go around it. If the drug has a low molecular weight and is lipophilic, the lipid cell membrane is not a barrier to drug diffusion and absorption. Passive diffusion is the process by which molecules spontaneously diffuse from a region of higher concentration to a region of lower concentration. This process is passive because no external energy is expended. In Fig. 4­4, drug molecules move forward and back across a membrane. If the two sides have the same drug concentration, forward­moving drug molecules are balanced by molecules moving back, resulting in no net transfer of drug. When one side is higher in drug concentration at any given time, the number of forward­ moving drug molecules will be higher than the number of backward­moving molecules; the net result will be a transfer of molecules to the alternate Downloaded 2024­9­11 12:33 A Your IP is 49.151.13.23 side downstream Chapter from the 4: Physiologic concentration Factors gradient, Related to as indicated Drug Absorption, in theM. Phillip Gerkby the big arrow. The rate of transfer is called flux and is represented figure Page 7 by a / 51 vector to show its direction in space. The tendency of molecules to move in all directions ©2024 McGraw Hill. All Rights Reserved. Terms Use Privacy Policy Notice Accessibility is natural because molecules possess kinetic energy and constantly collide with one another in space. Only left and right molecule movements are shown in Fig. 4­4, because movement of molecules in other directions will not result in concentration changes due to the limitation of the container wall. Theoretically, a lipophilic drug may pass through the cell or go around it. If the drug has a low molecular weight and is lipophilic, the lipid cell membrane is not a barrier to drug diffusion and absorption. Passive diffusion is the process by which molecules spontaneously diffuse from a region of higher concentration to a region of lower concentration. This process is passive because no external energy is expended. In Fig. 4­4, drug molecules Access Provided by: move forward and back across a membrane. If the two sides have the same drug concentration, forward­moving drug molecules are balanced by molecules moving back, resulting in no net transfer of drug. When one side is higher in drug concentration at any given time, the number of forward­ moving drug molecules will be higher than the number of backward­moving molecules; the net result will be a transfer of molecules to the alternate side downstream from the concentration gradient, as indicated in the figure by the big arrow. The rate of transfer is called flux and is represented by a vector to show its direction in space. The tendency of molecules to move in all directions is natural because molecules possess kinetic energy and constantly collide with one another in space. Only left and right molecule movements are shown in Fig. 4­4, because movement of molecules in other directions will not result in concentration changes due to the limitation of the container wall. FIGURE 4­4 Passive diffusion of molecules. Molecules in solution diffuse randomly in all directions. As molecules diffuse from left to right and vice versa (small arrows), a net diffusion from the high­concentration side to the low­concentration side results. This results in a net flux (J) to the right side. Flux is measured in mass per unit time (eg, ng/min). Passive diffusion is the major absorption process for most drugs. The driving force for passive diffusion is higher drug concentrations, typically on the mucosal side compared to the blood (serosal) side as in the case of oral drug absorption. According to Fick’s law of diffusion, drug molecules diffuse from a region of high drug concentration to a region of low drug concentration. (4.1) where dQ/dt = rate of diffusion, D = diffusion coefficient, A = surface area of membrane, K = lipid–water partition coefficient of drug in the biologic membrane that controls drug permeation, h = membrane thickness, and CGI − Cp = difference between the concentrations of drug in the GI tract and in the plasma. Because the drug distributes rapidly into a large volume after entering the blood, the concentration of drug in the blood initially is quite low with respect to the concentration at the site of drug absorption. For example, a drug is usually given in milligram doses so that the drug concentration at the absorption site maybe in mg/mL, whereas plasma drug concentrations are often in the microgram­per­milliliter or nanogram­per­milliliter range. If the drug is given orally, then CGI >> Cp. A large concentration gradient is maintained until most of the drug is absorbed, thus driving drug molecules from the GI tract into the plasma. Given Fick’s law of diffusion, several other factors may influence the rate of passive diffusion of drugs. For example, the degree of lipid solubility of the drug influences the rate of drug absorption. The partition coefficient, K, represents the lipid–water partitioning of a drug across a membrane such as the mucosa. Drugs that are more lipid soluble have a larger K value. The surface area, A, of the membrane also influences the rate of absorption. Drugs may be absorbed from most areas of the GI tract. However, the duodenal area of the small intestine shows the most rapid drug absorption, due to such anatomic features as villi and microvilli, which provide a large surface area. These villi are less abundant in other areas of the GI tract. The thickness of the membrane, h, is generally a constant1 for any particular absorption site. Drugs usually diffuse very rapidly through capillary plasma membranes in the vascular compartments, in contrast to diffusion through plasma membranes of capillaries in the brain. In the brain, the capillaries are densely lined with glial cells, so a drug diffuses slowly into the brain as if a thick lipid membrane exists. The term blood–brain barrier is used to describe the slow diffusion of water­soluble molecules across capillary plasma membranes into the brain. However, in certain disease states such as meningitis, these membranes may be disrupted or become more permeable to drug diffusion. The diffusion coefficient, D, is a constant for each drug and is defined as the amount of a drug that diffuses across a membrane of a given unit area per unit time when the concentration gradient is unity. The dimensions of D are area per unit time—for example, cm2/sec. Because D, A, K, and h are constants under usual conditions for absorption, a combined constant P or permeability coefficient may be defined. (4.2) Downloaded 2024­9­11 12:33 A Your IP is 49.151.13.23 Chapter 4: Physiologic Factors Related to Drug Absorption, Phillip M. Gerk Page 8 / 51 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Furthermore, in Equation 4.1 the drug concentration in the plasma, Cp, is extremely small compared to the drug concentration in the GI tract, CGI. If Cp is negligible and P is substituted into Equation 4.1, the following relationship for Fick’s law is obtained: The diffusion coefficient, D, is a constant for each drug and is defined as the amount of a drug that diffuses across a membrane of a given unit area per unit time when the concentration gradient is unity. The dimensions of D are area per unit time—for example, cm2/sec. Access Provided by: Because D, A, K, and h are constants under usual conditions for absorption, a combined constant P or permeability coefficient may be defined. (4.2) Furthermore, in Equation 4.1 the drug concentration in the plasma, Cp, is extremely small compared to the drug concentration in the GI tract, CGI. If Cp is negligible and P is substituted into Equation 4.1, the following relationship for Fick’s law is obtained: (4.3) Equation 4.3 is an expression for a first­order process. In practice, the extravascular absorption of most drugs tends to be a first­order absorption process. Moreover, because of the large concentration gradient between CGI and Cp, the rate of drug absorption is usually more rapid than the rate of drug elimination. Many drugs have both lipophilic and hydrophilic chemical substituents. Those drugs that are more lipid soluble tend to traverse cell membranes more easily than less lipid­soluble or more water­soluble molecules. For drugs that act as weak electrolytes, such as weak acids and bases, the extent of ionization influences the drug’s diffusional permeability. The ionized species of the drug contains a charge and is more water soluble than the nonionized species of the drug, which is more lipid soluble. The extent of ionization of a weak electrolyte will depend on both the pKa of the drug and the pH of the medium in which the drug is dissolved. Henderson and Hasselbalch used the following expressions pertaining to weak acids and weak bases to describe the relationship between pKa and pH: For weak acids, (4.4) For weak bases, (4.5) With Equations 4.4 and 4.5, the proportion of free acid or free base existing as the nonionized species may be determined at any given pH, assuming the pKa for the drug is known. For example, at a plasma pH of 7.4, salicylic acid (pKa = 3.0) exists mostly in its ionized or water­soluble form, as shown below: In a simple system, the total drug concentration on either side of a membrane should be the same at equilibrium, assuming Fick’s law of diffusion is the only distribution factor involved. For diffusible drugs, such as nonelectrolyte drugs or drugs that do not ionize, the drug concentrations on either side of the membrane are the same at equilibrium. However, for electrolyte drugs or drugs that ionize, the total drug concentrations on either side of the membrane are not equal at equilibrium if the pH of the medium differs on respective sides of the membrane. For example, consider the concentration of salicylic acid (pKa = 3.0) in the stomach (pH 1.2) as opposed to its concentration in the plasma (pH 7.4) (Fig. 4­5). According to the Henderson–Hasselbalch equation (Equation 4.4) for weak acids, at pH 7.4 and at pH 1.2, salicylic acid exists in the ratios that follow. FIGURE 4­5 Model for the distribution of an orally administered weak electrolyte drug such as salicylic acid. Downloaded 2024­9­11 12:33 A Your IP is 49.151.13.23 Chapter 4: Physiologic Factors Related to Drug Absorption, Phillip M. Gerk Page 9 / 51 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Henderson–Hasselbalch equation (Equation 4.4) for weak acids, at pH 7.4 and at pH 1.2, salicylic acid exists in the ratios that follow. FIGURE 4­5 Access Provided by: Model for the distribution of an orally administered weak electrolyte drug such as salicylic acid. In the plasma, at pH 7.4 In gastric juice, at pH 1.2 The total drug concentration on either side of the membrane is determined as shown in Table 4­3. TABLE 4­3 Relative Concentrations of Salicylic Acid as Affected by pH Drug Gastric Juice (pH 1.2) Plasma (pH 7.4) RCOOH 1.0000 1 RCOO− 0.0158 25,100 Total drug concentration 1.0158 25,101 Thus, the pH affects distribution of salicylic acid (RCOOH) and its salt (RCOO−) across cell membranes. It is assumed that the acid, RCOOH, is freely permeable and the salt, RCOO−, is not permeable across the cell membrane. In this example, the total concentration of salicylic acid at equilibrium is approximately 25,000 times greater in the plasma than in the stomach (see Table 4­3). These calculations can also be applied to weak bases, using Equation 4.5. According to the pH­partition hypothesis, if the pH on one side of a cell membrane differs from the pH on the other side of the membrane, then (1) the drug (weak acid or base) will ionize to different degrees on respective sides of the membrane; (2) the total drug concentrations (ionized plus nonionized drug) on either side of the membrane will be unequal; and (3) the compartment in which the drug is more highly ionized will contain the greater total drug concentration. For these reasons, a weak acid (such as salicylic acid) will be more rapidly absorbed from the stomach (pH 1.2) than a weak base (such as quinidine). Another factor that can influence drug concentrations on either side of a membrane is a particular affinity of the drug for a tissue component, which prevents the drug from moving freely back across the cell membrane. For example, a drug such as dicumarol binds to plasma protein, and digoxin binds to tissue protein. In each case, the protein­bound drug does not move freely across the cell membrane. Drugs such as chlordane are very lipid soluble and will partition into adipose (fat) tissue. In addition, a drug such as tetracycline might form a complex with calcium in the bones and teeth. Finally, a drug may concentrate in a tissue due to a specific uptake or active transport process. Such processes have been demonstrated for iodide in thyroid tissue, potassium in the intracellular water, and certain catecholamines into adrenergic storage sites. Such drugs may have a higher total drug concentration on the side where binding occurs, yet the free drug concentration that diffuses across cell membranes will be the same on both sides of the membrane. Instead of diffusing into the cell, drugs can also diffuse into the spaces around the cell as an absorption mechanism. In paracellular drug absorption, drug molecules smaller than 500 MW diffuse through the tight junctions, or spaces between intestinal epithelial cells. Generally, paracellular drug absorption is very Downloaded slow, being 2024­9­11 12:33limited A YourbyIP tight junctions between cells. For example, if mannitol is dosed orally, it would be absorbed minimally through is 49.151.13.23 Chapter 4: Physiologic Factors Related to Drug Absorption, Phillip M. Gerk this route; mannitol has very, very low oral bioavailability. Page 10 / 51 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Carrier­Mediated Transport thyroid tissue, potassium in the intracellular water, and certain catecholamines into adrenergic storage sites. Such drugs may have a higher total drug concentration on the side where binding occurs, yet the free drug concentration that diffuses across cell membranes will be the same on both sides of the membrane. Access Provided by: Instead of diffusing into the cell, drugs can also diffuse into the spaces around the cell as an absorption mechanism. In paracellular drug absorption, drug molecules smaller than 500 MW diffuse through the tight junctions, or spaces between intestinal epithelial cells. Generally, paracellular drug absorption is very slow, being limited by tight junctions between cells. For example, if mannitol is dosed orally, it would be absorbed minimally through this route; mannitol has very, very low oral bioavailability. Carrier­Mediated Transport Enterocytes are simple columnar epithelial cells that line the intestinal walls in the small intestine and colon. They express various drug transporters, are connected by tight junctions, and often play an important role in determining the rate and extent of drug absorption. Uptake transporters move drug molecules into the blood and increase plasma drug concentration, whereas efflux transporters move drug molecules back into the gut lumen and reduce systemic drug absorption. These cells also express some drug­metabolizing enzymes, and can contribute to presystemic drug metabolism (Doherty and Charman, 2002). Theoretically, a lipophilic drug may either pass through the cell or go around it. If the drug has a low molecular weight and is lipophilic, the lipid cell membrane is not a barrier to drug diffusion and absorption. In the intestine, drugs and other molecules can go through the intestinal epithelial cells by either diffusion or a carrier­mediated mechanism. Numerous specialized carrier­mediated transport systems are present in the body, especially in the intestine for the absorption of ions and nutrients required by the body. Active Transport Active transport is a carrier­mediated transmembrane process that plays an important role in the GI absorption and in urinary and biliary secretion of many drugs and metabolites. A few lipid­insoluble drugs that resemble natural physiologic metabolites (such as 5­fluorouracil) are absorbed from the GI tract by this process. Active transport is characterized by the ability to transport drug against a concentration gradient—that is, from regions of low drug concentrations to regions of high drug concentrations. Therefore, this is an energy­consuming system. In addition, active transport is a specialized process requiring a carrier that binds the drug to form a carrier–drug complex that shuttles the drug across the membrane and then dissociates the drug on the other side of the membrane (Fig. 4­6). FIGURE 4­6 Hypothetical carrier­mediated transport process. The carrier molecule may be highly selective for the drug molecule. If the drug structurally resembles a natural substrate that is actively transported, then it is likely to be actively transported by the same carrier mechanism. Therefore, drugs of similar structure may compete for sites of adsorption on the carrier. Furthermore, because only a fixed number of carrier molecules are available, all the binding sites on the carrier may become saturated if the drug concentration gets very high. A comparison between the rate of drug absorption and the concentration of drug at the absorption site is shown in Fig. 4­7. Notice that for a drug absorbed by passive diffusion, the rate of absorption increases in a linear relationship to drug concentration (first­ order rate). In contrast, for drugs that are absorbed by a carrier­mediated process, the rate of drug absorption increases with drug concentration until the carrier molecules are completely saturated. At higher drug concentrations, the rate of drug absorption remains constant, or zero order, as expected in Michaelis­Menten kinetics. FIGURE 4­7 Comparison of the rates of drug absorption of a drug absorbed by passive diffusion (line A) and a drug absorbed by a carrier­mediated system (line B). Downloaded 2024­9­11 12:33 A Your IP is 49.151.13.23 Chapter 4: Physiologic Factors Related to Drug Absorption, Phillip M. Gerk Page 11 / 51 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility expected in Michaelis­Menten kinetics. FIGURE 4­7 Access Provided by: Comparison of the rates of drug absorption of a drug absorbed by passive diffusion (line A) and a drug absorbed by a carrier­mediated system (line B). Several transport proteins are expressed in the intestinal epithelial cells (Suzuki and Sugiyama, 2000; Takano et al, 2006) (Fig. 4­8). Although some transporters facilitate absorption, other transporters such as P­gp may effectively inhibit drug absorption. P­gp (also known as MDR1), an energy­ dependent, membrane­bound protein, is an efflux transporter that mediates the secretion of compounds from inside the cell back out into the intestinal lumen, thereby limiting overall absorption (see Chapter 21). Thus, drug absorption may be reduced or increased by the presence or absence of efflux proteins. The role of efflux proteins is generally believed to be a defense mechanism for the body to excrete and reduce drug accumulation. FIGURE 4­8 Localization of efflux transporters and PEPT1 in intestinal epithelial cell. (Reproduced with permission from Takano M, Yumoto R, Murakami T. Expression and function of efflux drug transporters in the intestine. Pharmacol Ther 2006 Jan;109(1­2):137–161.) P­gp is expressed also in other tissues such as the blood–brain barrier, liver, and kidney, where it limits drug penetration into the brain, mediates biliary drug secretion, and mediates renal tubular drug secretion, respectively. Efflux pumps are present throughout the body and are involved in transport of a diverse group of hydrophobic drugs, natural products, and peptides. Many drugs and chemotherapeutic agents, such as cyclosporin A, verapamil, terfenadine, fexofenadine, and most HIV­1 protease inhibitors, are substrates of P­gp (see Chapter 21). In addition, individual genetic differences in intestinal absorption may be the result of genetic differences in P­gp and other transporters. Facilitated Diffusion Facilitated diffusion is also a carrier­mediated transport system, differing from active transport in that the drug moves along a concentration gradient (ie, moves from a region of high drug concentration to a region of low drug concentration). Therefore, this system does not require energy input. However, because this system is carrier mediated, it is saturable and structurally selective for the drug and shows competition kinetics for drugs of similar structure. In terms of drug absorption, facilitated diffusion seems to play a very minor role. Transporters and Carrier­Mediated Intestinal Absorption Downloaded 2024­9­11 12:33 A Your IP is 49.151.13.23 Various carrier­mediated Chapter systems 4: Physiologic Factors (transporters) Related to Drugare present atPhillip Absorption, the intestinal M. Gerkbrush border and basolateral membrane for the absorption Pageof specific 12 / 51 ©2024 ions andMcGraw Hill. nutrients All Rights essential for Reserved. Terms the body (Tsuji and of Use 1996). Tamai, Privacy Policy Both Notice influx Accessibility and efflux transporters are present in the brush border and basolateral membrane that will increase drug absorption (influx transporter) or decrease drug absorption (efflux transporter). Facilitated diffusion is also a carrier­mediated transport system, differing from active transport in that the drug moves along a concentration gradient (ie, moves from a region of high drug concentration to a region of low drug concentration). Therefore, this system does not require energy input. However, because this system is carrier mediated, it is saturable and structurally selective for the drug and shows competition kinetics for drugs of Access Provided by: similar structure. In terms of drug absorption, facilitated diffusion seems to play a very minor role. Transporters and Carrier­Mediated Intestinal Absorption Various carrier­mediated systems (transporters) are present at the intestinal brush border and basolateral membrane for the absorption of specific ions and nutrients essential for the body (Tsuji and Tamai, 1996). Both influx and efflux transporters are present in the brush border and basolateral membrane that will increase drug absorption (influx transporter) or decrease drug absorption (efflux transporter). Uptake transporters For convenience, influx transporters were referred to as those that enhance absorption as uptake transporters and those that cause drug outflow as efflux transporters. However, this concept is too simple and inadequate to describe the roles of many transporters that have bidirectional efflux and other functions related to their location in the membrane. Recent progress has been made in understanding the genetic role of membrane transporters in drug safety and efficacy. In particular, more than 400 membrane transporters in two major superfamilies—ATP­binding cassette (ABC) and solute carrier (SLC)—have been annotated in the human genome. Many of these transporters have been cloned, characterized, and localized in the human body including the GI tract. The subject was reviewed by The International Transporter Consortium (ITC) (Giacomini, 2010). Many drugs are absorbed by carrier systems because of the structural similarity to natural substrates or simply because they encounter the transporters located in specific part of the GI tract (Table 4­4). The small intestine expresses a variety of uptake transporters (see Fig. 4­2) for amino acids, peptides, hexoses, organic anions, organic cations, nucleosides, and other nutrients (Tsuji and Tamai, 1996; Giacomini, 2010). Among these uptake (absorptive) transporters are the intestinal oligopeptide transporter, or di­/tripeptide transporter, PEPT1 has potential for enhancing intestinal absorption of peptide drugs. The expression and function of PEPT1 (gene symbol SLC15A1) are now well analyzed for this application. Proteins given orally are digested in the GI tract to produce a variety of short­chain peptides; these di­ and tripeptides could be taken up by enterocytes and the proton/peptide cotransporter (PepT1) localized on the brush­border membrane. These uptake transporters are located at the brush border as well as in the basolateral membrane to allow efficient absorption of essential nutrients into the body. Uptake transporters such as those for hexoses and amino acids also favor absorption (see arrows as shown in Fig. 4­7). TABLE 4­4 Intestine Transporters and Examples of Drugs Transported Transporter Examples Amino acid transporter Gabapentin D­Cycloserine Methyldopa Baclofen L­dopa Oligopeptide transporter Cefadroxil Cephradine Cefixime Ceftibuten Cephalexin Captopril Lisinopril Thrombin inhibitor Phosphate transporter Fostomycin Foscarnet Bile acid transporter S3744 Glucose transporter p­Nitrophenyl­β­d­glucopyranoside P­glycoprotein efflux Etoposide Vinblastine Downloaded 2024­9­11 12:33 A Your IP is 49.151.13.23Cyclosporin A Chapter 4: Physiologic Factors Related to Drug Absorption, Phillip M. Gerk Page 13 / 51 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Monocarboxylic acid transporter Salicylic acid Benzoic acid Pravastatin orally are digested in the GI tract to produce a variety of short­chain peptides; these di­ and tripeptides could be taken up by enterocytes and the proton/peptide cotransporter (PepT1) localized on the brush­border membrane. These uptake transporters are located at the brush border as well as in the basolateral membrane to allow efficient absorption of essential nutrients into the body. Uptake transporters such as those for hexoses and Access Provided by: amino acids also favor absorption (see arrows as shown in Fig. 4­7). TABLE 4­4 Intestine Transporters and Examples of Drugs Transported Transporter Examples Amino acid transporter Gabapentin D­Cycloserine Methyldopa Baclofen L­dopa Oligopeptide transporter Cefadroxil Cephradine Cefixime Ceftibuten Cephalexin Captopril Lisinopril Thrombin inhibitor Phosphate transporter Fostomycin Foscarnet Bile acid transporter S3744 Glucose transporter p­Nitrophenyl­β­d­glucopyranoside P­glycoprotein efflux Etoposide Vinblastine Cyclosporin A Monocarboxylic acid transporter Salicylic acid Benzoic acid Pravastatin Data from Tsuji A, Tamai I. Carrier­mediated intestinal transport of drugs, Pharm Res 1996 Jul;13(7):963–977. Efflux transporters Many of the efflux transporters in the GI tract are membrane proteins located strategically in membranes to protect the body from influx of undesirable compounds. A common example is MDR1 or P­gp (alias), which has the gene symbol ABCB1. P­gp is an example of the ABC subfamily. MDR1 is one of the many proteins known as multidrug­resistance­associated protein. It is important in pumping drugs out of cells and causing treatment resistance in some cell lines (see Chapter 21). P­gp has been identified in the intestine and reduces apparent intestinal epithelial cell permeability from lumen to blood for various lipophilic or cytotoxic drugs. P­gp is highly expressed on the apical surface of superficial columnar epithelial cells of the ileum and colon, and expression decreases proximally into the jejunum, duodenum, and stomach. Takano et al (2006) reported that P­gp is present in various human tissues and ranked as follows: (1) adrenal medulla (relative level to that in KB­3­1 cells, >500­fold); (2) adrenal (160­fold); (3) kidney medulla (75­fold); (4) kidney (50­fold); (5) colon (31­fold); (6) liver (25­fold); (7) lung, jejunum, and rectum (20­fold); (8) brain (12­fold); (9) prostate (8­fold); and so on, including skin, esophagus, stomach, ovary, muscle, heart, and kidney cortex. The widespread presence of P­gp in the body appears to be related to its defensive role in effluxing drugs and other xenobiotics out of different cells and vital body organs. This transporter is sometimes called an efflux transporter while others are better described as “influx” proteins. P­gp has the remarkable ability to efflux drug out of many types of cells including endothelial lumens of capillaries. The Downloaded expression 2024­9­11 of P­gp 12:33 is often A Your IP triggered in many cancer cells making them drug resistant due to drug efflux. is 49.151.13.23 Chapter 4: Physiologic Factors Related to Drug Absorption, Phillip M. Gerk Page 14 / 51 For many ©2024 GI transporters, McGraw the transport Hill. All Rights Reserved.of a Terms drug is of often Usebidirectional (Fig. 4­9), Privacy Policy and whether Notice the transporter causes drug absorption or exsorption Accessibility depends on which direction the flux dominates with regard to a particular drug at a given site. An example of how P­gp affects drug absorption can be seen with the drug digoxin. P­gp is present in the liver and the GI tract. In Caco­2 cells and other model systems, P­gp is known to efflux drug out of the follows: (1) adrenal medulla (relative level to that in KB­3­1 cells, >500­fold); (2) adrenal (160­fold); (3) kidney medulla (75­fold); (4) kidney (50­fold); (5) colon (31­fold); (6) liver (25­fold); (7) lung, jejunum, and rectum (20­fold); (8) brain (12­fold); (9) prostate (8­fold); and so on, including skin, esophagus, stomach, ovary, muscle, heart, and kidney cortex. The widespread presence of P­gp in the body appears to be related to its defensive role in effluxing Access Provided by: drugs and other xenobiotics out of different cells and vital body organs. This transporter is sometimes called an efflux transporter while others are better described as “influx” proteins. P­gp has the remarkable ability to efflux drug out of many types of cells including endothelial lumens of capillaries. The expression of P­gp is often triggered in many cancer cells making them drug resistant due to drug efflux. For many GI transporters, the transport of a drug is often bidirectional (Fig. 4­9), and whether the transporter causes drug absorption or exsorption depends on which direction the flux dominates with regard to a particular drug at a given site. An example of how P­gp affects drug absorption can be seen with the drug digoxin. P­gp is present in the liver and the GI tract. In Caco­2 cells and other model systems, P­gp is known to efflux drug out of the enterocyte. Digoxin was previously known to have erratic/incomplete absorption or bioavailability problems. While reported bioavailability issues were attributed to formulation or other factors, it is also now known that knocking out the P­gp gene in mice increases bioavailability of the drug. In addition, human P­gp genetic polymorphisms occur. Hoffmeyer et al (2000) demonstrated that a polymorphism in exon 26 (C3435T) resulted in reduced intestinal P­gp, leading to increased oral bioavailability of digoxin in the subject involved. However, direct determination of P­gp substrate in vivo is not always readily possible. Most early determinations are done using in vitro cell assay methods, or in vivo studies involving a cloned animal with the gene knocked out such as the P­gp, a knock­out (KO) mouse, for example, P­gp (−/−), which is the most sensitive method to identify P­gp substrates. Changes in the expression of P­gp may be triggered by diseases or other drugs, contributing to variability in P­gp activity and variable plasma drug concentrations after a given dose is administered. Results from in vitro and preclinical (animal) studies may need to be verified through clinical drug–drug interaction studies to establish the role of P­gp in the oral bioavailability of a drug. FIGURE 4­9 Diagram showing possible directional movement of a substrate drug by a transporter. The breast cancer resistance protein (BCRP; gene symbol ABCG2) is like P­gp in that it is also found in many important fluid barrier layers, including the intestine, liver, kidney, and brain. BCRP also transports many drugs out of cells, working (like P­gp) to keep various compounds out of the body (by decreasing their absorption) or helping to eliminate them. Drugs transported by BCRP include many anticancer drugs (methotrexate, irinotecan, mitoxantrone), statins (rosuvastatin), as well as nitrofurantoin and various sulfated metabolites of drugs and endogenous compounds. The FDA requires all investigational new drugs to be tested for their potential activity as substrates of both P­gp and BCRP, and also recommends determining if they are inhibitors (Huang and Zhang, 2012). FREQUENTLY ASKED QUESTIONS What is the effect of intestinal P­gp on the blood level of the substrate drug digoxin when a substrate inhibitor (ketoconazole) is present? According to the diagram in Fig. 4­9, in which direction is P­gp pumping the drug? Is P­gp acting as an efflux transporter in this diagram? Why is it too simple to classify transporters based on an “absorption” and “exsorption” concept? Would a drug transport process involving ABC transporter be considered a passive or active transport process? How does a transporter influence the level of drug within the cell? P­gp affects the bioavailability of many substrate drugs listed in Table 4­5. P­gp inhibitors should be carefully evaluated before coadministration with a P­gp substrate drug. Other transporters are also present in the intestines (Tsuji and Tamai, 1996). For example, many oral cephalosporins are absorbed through amino acid transporters. Cefazolin, a parenteral­only cephalosporin, is not available orally because it cannot be absorbed to a Downloaded 2024­9­11 significant degree through 12:33 A Your IP is 49.151.13.23 this mechanism. Chapter 4: Physiologic Factors Related to Drug Absorption, Phillip M. Gerk Page 15 / 51 ©2024 TABLEMcGraw 4­5 Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Reported Substrates of P­gp—A Member of ATP­Binding Cassette (ABC) Transporters  How does a transporter influence the level of drug within the cell? Access Provided by: P­gp affects the bioavailability of many substrate drugs listed in Table 4­5. P­gp inhibitors should be carefully evaluated before coadministration with a P­gp substrate drug. Other transporters are also present in the intestines (Tsuji and Tamai, 1996). For example, many oral cephalosporins are absorbed through amino acid transporters. Cefazolin, a parenteral­only cephalosporin, is not available orally because it cannot be absorbed to a significant degree through this mechanism. TABLE 4­5 Reported Substrates of P­gp—A Member of ATP­Binding Cassette (ABC) Transporters Acebutolol, acetaminophen, actinomycin d, h­acetyldigoxin, amitriptyline, amprenavir, apafant, asimadoline, atenolol, atorvastatin, azidopine, azidoprocainamide methiodide, azithromycin Benzo(a)pyrene, betamethasone, bisantrene, bromocriptine, bunitrolol, calcein­AM Camptothecin, carbamazepine, carvedilol, celiprolol, cepharanthin, cerivastatin, chloroquine, chlorpromazine, chlorothiazide, clarithromycin, colchicine, corticosterone, cortisol, cyclosporin A Daunorubicin (daunomycin), debrisoquine, desoxycorticoster one, dexamethasone, digitoxin Digoxin, diltiazem, dipyridamole, docetaxel, dolastatin 10, domperidone, doxorubicin (adriamycin) Eletriptan, emetine, endosulfan, erythromycin, estradiol, estradiol­17h­d­glucuronide, etoposide (VP­16) Fexofenadine, gf120918, grepafloxacin Hoechst 33342, hydroxyrubicin, imatinib, indinavir, ivermectin Levofloxacin, loperamide, losartan, lovastatin Methadone, methotrexate, methylprednisolone, metoprolol, mitoxantrone, monensin Morphine, 99mtc­sestamibi N­desmethyltamoxifen, nadolol, nelfinavir, nicardipine, nifedipine, nitrendipine, norverapamil Olanzapine, omeprazole PSC­833 (valspodar), perphenazine, prazosin, prednisone, pristinamycin IA, puromycin Quetiapine, quinidine, quinine Ranitidine, reserpine Rhodamine 123, risperidone, ritonavir, roxithromycin Saquinavir, sirolimus, sparfloxacin, sumatriptan, Tacrolimus, talinolol, tamoxifen, taxol (paclitaxel), telithromycin, terfenadine, timolol, toremifene Tributylmethylammonium, trimethoprim Valinomycin, vecuronium, verapamil, vinblastine Vincristine, vindoline, vinorelbine Adapted with permission from Takano M, Yumoto R, Murakami T. Expression and function of efflux drug transporters in the intestine. Pharmacol Ther 2006 Jan;109(1–2):137–161. FREQUENTLY ASKED QUESTIONS The bioavailability of an antitumor drug is provided in the package insert. Why is it important to know whether the drug is an efflux transporter substrate or not? Can the expression of efflux transporter in a cell change as the disease progresses? Why is blockade of efflux transporter efflux of a drug, its glucuronide, or sulfate metabolite into the bile clinically important? Clinical Examples of Transporter Impact Multidrug resistance (MDR) to cancer cells has been linked to efflux transporter proteins such as P­gp that can efflux or pump out chemotherapeutic agents from the cells (Sauna et al, 2001). Paclitaxel (Taxol) is an example of coordinated metabolism, efflux, and triggering of hormone nuclear receptor to induce efflux protein (Fig. 4­10). P­gp (see MDR1 in Fig. 4­2) is responsible for 85% of paclitaxel excretion back into the GI tract (Synold et al, Downloaded 2024­9­11 2001). Paclitaxel activates12:33 A Your IP the pregnane is 49.151.13.23 X receptor (also known as PXR, or alternatively as steroid X receptor [SXR]), which in turn induces MDR1 Chapter 4: Physiologic Factors Related to Drug Absorption, Phillip M. Gerk Page 16 / 51 transcription ©2024 McGraw Hill. All Rights Reserved. Terms offurther and P­gp expression, resulting in even Use excretion of paclitaxel Privacy Policy Noticeinto the intestinal fluid. Paclitaxel also induces CYP3A4 and CYP2C8 Accessibility transcription, resulting in increased paclitaxel metabolism. Thus, in response to a xenobiotic challenge, PXR can induce both a first line of defense (intestinal excretion) and a backup system (hepatic drug inactivation) that limits exposure to potentially toxic compounds. In contrast to paclitaxel, Clinical Examples of Transporter Impact Access Provided by: Multidrug resistance (MDR) to cancer cells has been linked to efflux transporter proteins such as P­gp that can efflux or pump out chemotherapeutic agents from the cells (Sauna et al, 2001). Paclitaxel (Taxol) is an example of coordinated metabolism, efflux, and triggering of hormone nuclear receptor to induce efflux protein (Fig. 4­10). P­gp (see MDR1 in Fig. 4­2) is responsible for 85% of paclitaxel excretion back into the GI tract (Synold et al, 2001). Paclitaxel activates the pregnane X receptor (also known as PXR, or alternatively as steroid X receptor [SXR]), which in turn induces MDR1 transcription and P­gp expression, resulting in even further excretion of paclitaxel into the intestinal fluid. Paclitaxel also induces CYP3A4 and CYP2C8 transcription, resulting in increased paclitaxel metabolism. Thus, in response to a xenobiotic challenge, PXR can induce both a first line of defense (intestinal excretion) and a backup system (hepatic drug inactivation) that limits exposure to potentially toxic compounds. In contrast to paclitaxel, docetaxel is a closely related antineoplastic agent that does not activate PXR but has a much better absorption profile. FIGURE 4­10 Mechanism of coordinated efflux and metabolism of paclitaxel by PXR (SXR). (Reproduced with permission from Synold TW, Dussault I, Forman BM. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med 2001 May;7(5):584–590.) Mutations of other transporters, particularly those involved in reuptake of serotonin, dopamine, and gamma­aminobutyric acid (GABA), are presently being studied with regard to clinically relevant changes in drug response. Pharmacogenetic variability in these transporters is an important consideration in patient dosing. When therapeutic failures occur, the following questions should be asked: (1) Is the drug a substrate for P­gp and/or CYP3A4? (2) Is the drug being coadministered with anything that inhibits P­gp and/or CYP3A4? For example, grapefruit juice and many drugs can affect drug metabolism and oral absorption. Vesicular Transport Vesicular transport is the process of engulfing particles or dissolved materials by the cell. Pinocytosis and phagocytosis are forms of vesicular transport that differ by the type of material ingested. Pinocytosis refers to the engulfment of small solutes or fluid, whereas phagocytosis refers to the engulfment of larger particles or macromolecules, generally by macrophages. Endocytosis and exocytosis are the processes of moving specific macromolecules into and out of a cell, respectively. During pinocytosis, phagocytosis, or transcytosis, the cell membrane invaginates to surround the material and then engulfs the material, incorporating it inside the cell (Fig. 4­11). Subsequently, the cell membrane containing the material forms a vesicle or vacuole within the cell. Transcytosis is the process by which various macromolecules are transported across the interior of a cell. In transcytosis, the vesicle fuses with the plasma membrane to release the encapsulated material to another side of the cell. Vesicles are employed to intake the macromolecules on one side of the cell, draw them across the cell, and eject them on the other side. Transcytosis (sometimes referred to as vesicular transport) is the proposed process for the absorption of 2024­9­11 Downloaded orally administered 12:33 A Sabin polio Your IP vaccine and various large proteins. is 49.151.13.23 Chapter 4: Physiologic Factors Related to Drug Absorption, Phillip M. Gerk Page 17 / 51 ©20244­11 FIGURE McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Diagram showing exocytosis and endocytosis. During pinocytosis, phagocytosis, or transcytosis, the cell membrane invaginates to surround the material and then engulfs the material, incorporating it inside the cell (Fig. 4­11). Subsequently, the cell membrane containing the material forms a vesicle or vacuole within the cell. Transcytosis is the process by which various macromolecules are transported across the interior of a cell. In transcytosis, the vesicle fuses with the plasma membrane to Access Provided by: release the encapsulated material to another side of the cell. Vesicles are employed to intake the macromolecules on one side of the cell, draw them across the cell, and eject them on the other side. Transcytosis (sometimes referred to as vesicular transport) is the proposed process for the absorption of orally administered Sabin polio vaccine and various large proteins. FIGURE 4­11 Diagram showing exocytosis and endocytosis. Pinocytosis is a cellular process that permits the active transport of fluid from outside the cell through the membrane surrounding the cell into the inside of the cell. In pinocytosis, tiny incuppings called caveolae (little caves) in the surface of the cell close and then pinch off to form pinosomes, little fluid­filled bubbles, that are free within the cytoplasm of the cell. An example of exocytosis is the transport of a protein such as insulin from insulin­producing cells of the pancreas into the extracellular space. The insulin molecules are first packaged into intracellular vesicles, which then fuse with the plasma membrane to release the insulin outside the cell. Pore (Convective) Transport Very small molecules (such as urea, water, and sugars) are able to cross cell membranes rapidly, as if the membrane contained channels or pores. Although such pores have never been directly observed by microscopy, the model of drug permeation through aqueous pores is used to explain renal excretion of drugs and the uptake of drugs into the liver. A certain type of protein called a transport protein may form an open channel across the lipid membrane of the cell (see Fig. 4­2). Small molecules including drugs move through the channel by diffusion more rapidly than at other parts of the membrane. Ion­Pair Formation Strong electrolyte drugs are highly ionized or charged molecules, such as quaternary nitrogen compounds with extreme pKa values. Strong electrolyte drugs maintain their charge at all physiologic pH values and penetrate membranes poorly. When the ionized drug is linked with an oppositely charged ion, an ion pair is formed in which the overall charge of the pair is neutral. This neutral drug complex diffuses more easily across the membrane. For example, the formation of ion pairs to facilitate drug absorption has been demonstrated for propranolol, a basic drug that forms an ion pair with oleic acid, and quinine, which forms ion pairs with hexylsalicylate (Nienbert, 1989). An interesting application of ion pairs is the complexation of amphotericin B and DSPG (distearoylphosphatidylglycerol) in some amphotericin B/liposome products. Ion pairing may transiently alter distribution, reduce high plasma free drug concentration, and reduce renal toxicity. 1 The thickness of the membrane is generally a constant. However, under certain pathological conditions such as meningitis, drugs penetrate into the Downloaded 2024­9­11 12:33 A Your IP is 49.151.13.23 Chapter 4: Physiologic brain more quickly or in Factors the caseRelated of burns,todrugs Drugcan Absorption, permeatePhillip throughM. the Gerkskin more easily. Page 18 / 51 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility DRUG INTERACTIONS IN THE GASTROINTESTINAL TRACT example, the formation of ion pairs to facilitate drug absorption has been demonstrated for propranolol, a basic drug that forms an ion pair with oleic acid, and quinine, which forms ion pairs with hexylsalicylate (Nienbert, 1989). An interesting application of ion pairs is the complexation of amphotericin B and DSPG (distearoylphosphatidylglycerol) in some amphotericin Access Provided by: B/liposome products. Ion pairing may transiently alter distribution, reduce high plasma free drug concentration, and reduce renal toxicity. 1 The thickness of the membrane is generally a constant. However, under certain pathological conditions such as meningitis, drugs penetrate into the brain more quickly or in the case of burns, drugs can permeate through the skin more easily. DRUG INTERACTIONS IN THE GASTROINTESTINAL TRACT Many agents (drug or chemical substances) may have dual roles as substrate and/or inhibitor between CYP3A4 and P­glycoprotein, P­gp. Simultaneous administration of these agents results in an increase in the oral drug bioavailability of one or both of the drugs. Various drug–drug and drug–nutrient interactions involving oral bioavailability have been reported in human subjects (Thummel and Wilkinson, 1998; Di Marco et al, 2002; von Richter et al, 2004). Many commonly used medications (eg, dextromethorphan hydrobromide) and certain food groups (eg, grapefruit juice) are substrates both for the efflux transporter, P­gp, and for the CYP3A enzymes involved in biotransformation of drugs (see Chapter 21). Grapefruit juice also affects drug transport in the intestinal wall. Certain components of grapefruit juice (such as naringin and bergamottin) are responsible for the inhibition of P­gp and CYP3A. Di Marco et al (2002) demonstrated the inhibitory effect of grapefruit and Seville orange juice on the pharmacokinetics of dextromethorphan. Using dextromethorphan as the substrate, these investigators showed that grapefruit juice inhibits both CYP3A activity as well as P­gp resulting in an increased bioavailability of dextromethorphan. Grapefruit juice has been shown to increase the oral bioavailability of many drugs, such as cyclosporine or saquinavir, by inhibiting intestinal metabolism. Esomeprazole (Nexium) and omeprazole (Prilosec®) are proton pump inhibitors that inhibit gastric acid secretion, resulting an increased stomach pH. Esomeprazole and omeprazole may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (eg, ketoconazole, iron salts, and digoxin). Both esomeprazole and omeprazole are extensively metabolized in the liver by CYP2C19 and CYP3A4. The prodrug clopidogrel (Plavix) inhibits platelet aggregation entirely due to an active metabolite. Coadministration of clopidogrel with omeprazole, an inhibitor of CYP2C19, reduces the pharmacological activity of clopidogrel if given either concomitantly or 12 hours apart. The dual effect of a CYP isoenzyme and a transporter on drug absorption is not always easy to determine or predict based on pharmacokinetic studies alone. A well­studied example is the drug digoxin. Digoxin is minimally metabolized (CYP3A4), orally absorbed (Suzuki and Sugiyama, 2000), and a substrate for P­gp based on: 1. Human polymorphism single­nucleotide polymorphism (SNP) in exon 26 (C3435T) results in a reduced intestinal expression level of P­gp, along with increased oral bioavailability of digoxin. 2. Ketoconazole increases the oral bioavailability and shortens mean absorption time from 1.1 to 0.3 hour. Ketoconazole is a substrate and inhibitor of P­gp; P­gp can subsequently influence bioavailability. The influence of P­gp is not always easily detected unless studies are designed to investigate its presence. For this analysis, a drug is given orally and intravenously before and after administration of an inhibitor drug. The AUC of the drug is calculated for each case. For example, ketoconazole causes an increase in the oral bioavailability of the immunosuppressant tacrolimus from 0.14 to 0.30, without affecting hepatic bioavailability (0.96–0.97) (Suzuki and Sugiyama, 2000). Since hepatic bioavailability is similar, the increase in bioavailability from 0.14 to 0.30 is the result of ketoconazole suppression on P­gp. Mouly and Paine (2003) reported P­gp expression determined by Western blotting along the entire length of the human small intestine. They found that relative P­gp levels increased progressively from the proximal to the distal region. von Richter et al (2004) measured P­gp as well as CYP3A4 in paired human small intestine and liver specimens obtained from 15 patients. They reported that much higher levels of both P­gp (about seven times) and CYP3A4 (about three times) were found in the intestine than in the liver, suggesting the critical participation of intestinal P­gp in limiting oral drug bioavailability. The concept of drug–drug interactions has received increased attention in recent years, as they may be responsible for many drug therapy­induced medical problems (Johnson et al, 1999). FREQUENTLY ASKED QUESTIONS Animal studies are not definitive when extrapolated to humans. Why are animal studies or in vitro transport studies in human cells often Downloaded 2024­9­11 performed 12:33 to decide A Your whether IP is 49.151.13.23 a drug a P­gp substrate? Chapter 4: Physiologic Factors Related to Drug Absorption, Phillip M. Gerk Page 19 / 51 ©2024How McGraw wouldHill. youAll Rights Reserved. demonstrate Terms that digoxin of Use Privacy metabolism is solelyPolicy due to hepatic Notice extraction Accessibility and not due to intestinal extraction since both CYP3A4 and P­gp are present in the intestine in larger amounts? and CYP3A4 (about three times) were found in the intestine than in the liver, suggesting the critical participation of intestinal P­gp in limiting oral drug bioavailability. The concept of drug–drug interactions has received increased attention in recent years, as they may be responsible for many drug therapy­induced Access Provided by: medical problems (Johnson et al, 1999). FREQUENTLY ASKED QUESTIONS Animal studies are not definitive when extrapolated to humans. Why are animal studies or in vitro transport studies in human cells often performed to decide whether a drug is a P­gp substrate? How would you demonstrate that digoxin metabolism is solely due to hepatic extraction and not due to intestinal extraction since both CYP3A4 and P­gp are present in the intestine in larger amounts? ORAL DRUG ABSORPTION The oral route of administration is the most common and popular route of drug dosing. The oral dosage form must be designed to account for extreme pH ranges, the presence or absence of food, degradative enzymes, varying drug permeability in the different regions of the intestine, and motility of the GI tract. In this chapter we will discuss intestinal variables that affect absorption; dosage­form considerations are discussed in Chapters 7–10. Anatomic and Physiologic Considerations The normal physiologic processes of the alimentary canal may be affected by diet, contents of the GI tract, hormones, the visceral nervous system, disease, and drugs. Thus, drugs given by the enteral route for systemic absorption may be affected by the anatomy, physiologic functions, and contents of the alimentary tract. Moreover, the physical, chemical, and pharmacologic properties of the drug and the formulation of the drug product will also affect systemic drug absorption from the alimentary canal. The enteral system consists of the alimentary canal from the mouth to the anus (Fig. 4­12). The major physiologic processes that occur in the GI system are secretion, digestion, and absorption. Secretion includes the transport of fluid, electrolytes, peptides, and proteins into the lumen of the alimentary canal. Enzymes in saliva and pancreatic secretions are also involved in the digestion of carbohydrates and proteins. Other secretions, such as mucus, protect the linings of the lumen of the GI tract. Digestion is the breakdown of food constituents into smaller structures in preparation for absorption. Food constituents are mostly absorbed in the proximal area (duodenum) of the small intestine. The process of absorption is the entry of constituents from the lumen of the gut into the body. Absorption may be considered the net result of both lumen­to­blood and blood­to­lumen transport movements. FIGURE 4­12 Gastrointestinal tract. Downloaded 2024­9­11 12:33 A Your IP is 49.151.13.23 Chapter 4: Physiologic Factors Related to Drug Absorption, Phillip M. Gerk Page 20 / 51 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility movements. FIGURE 4­12 Access Provided by: Gastrointestinal tract. Drugs administered orally pass through various parts of the enteral canal, including the oral cavity, esophagus, and various parts of the GI tract. Residues eventually exit the body through the anus with the feces. The total transit time, including gastric emptying, small intestinal transit, and colonic transit, ranges from 0.4 to 5 days (Kirwan and Smith, 1974). The small intestine, particularly the duodenum area, is the most important site for drug absorption. Small intestine transit time (SITT) ranges from 3 to 4 hours for most healthy subjects. If absorption is not completed by the time a drug leaves the small intestine, absorption may be erratic or incomplete. The small intestine is normally filled with digestive juices and liquids, keeping the lumen contents fluid. In contrast, the fluid in the colon is reabsorbed, and the lumenal content in the colon is either semisolid or solid, making further drug dissolution and absorption erratic and difficult. The lack of the solubilizing effect of the chyme and digestive fluid contributes to a less favorable environment for drug absorption. Oral Cavity Saliva is the main secretion of the oral cavity, and it has a pH of about 7. Saliva contains ptyalin (salivary amylase), which digests starches. Mucin, a glycoprotein that lubricates food, is also secreted and may interact with drugs. About 1500 mL of saliva is secreted per day. The oral cavity can be used for the buccal absorption of lipid­soluble drugs such as fentanyl citrate (Actiq®) and nitroglycerin, also formulated for sublingual routes. Recently, orally disintegrating tablets (ODTs) have become available. These ODTs, such as aripiprazole (Abilify Discmelt®), rapidly disintegrate in the oral cavity in the presence of saliva. The resulting fragments, which are suspended in the saliva, are swallowed and the drug is then absorbed from the GI tract. A major advantage for ODTs is that the drug may be taken without water. In the case of the antipsychotic drug, aripiprazole, a nurse may give the drug in the form of an ODT (Abilify Discmelt) to a schizophrenic patient. The nurse can easily ascertain that the drug was taken and swallowed. Esophagus The esophagus connects the pharynx and the cardiac orifice of the stomach. The pH of the fluids in the esophagus is between 5 and 6. The lower part Downloaded 2024­9­11 12:33 A Your IP is 49.151.13.23 of the esophagus ends with the esophageal sphincter, which prevents acid reflux from the stomach. Tablets or capsules may lodge in this Page area, 21 causing Chapter 4: Physiologic Factors Related to Drug Absorption, Phillip M. Gerk / 51 local irritation. Very little drug dissolution occurs in the esophagus. ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Stomach a nurse may give the drug in the form of an ODT (Abilify Discmelt) to a schizophrenic patient. The nurse can easily ascertain that the drug was taken and swallowed. Access Provided by: Esophagus The esophagus connects the pharynx and the cardiac orifice of the stomach. The pH of the fluids in the esophagus is between 5 and