Anatomical And Physiological Considerations Of The Gastrointestinal Tract

The GIT is a highly specialized region of the body whose primary functions involve the processes of secretion, digestion, and absorption. Since all nutrients needed by the body, with the exception of oxygen, must first be ingested orally, then processed by the GIT, and then made available for absorption into the bloodstream, the GIT represents a significant barrier and interface with the environment. The primary defense mechanisms employed by the gut to rid it of noxious or irritating materials are vomiting and diarrhea. In fact, emesis is often a first approach to the treatment of oral poisoning. Diarrhea conditions, initiated by either a pathological state or a physiological mechanism, will result in the flushing away of toxins or bacteria or will represent the response to a stressful condition. Indeed, the GIT is often the first site of the body's response to stress, a fact readily appreciated by students taking a final exam! The nearly instinctive gut response to stress may be particularly pertinent to patients needing oral drug therapy. Since stress is a fact of our daily lives, and since any illness requiring drug therapy may to some degree be considered stressful, the implications of the body's response to stress and the resulting influence on drug absorption from the gut may be particularly pertinent.

Figure 1 illustrates the gross functional regions of the GIT (4). The liver, gallbladder, and pancreas secrete materials vital to the digestive and certain absorptive functions of the gut. The lengths of various regions of the GIT are presented in Table 1. The small intestine, comprising the duodenum, jejunum, and ileum, represents greater than 60% of the length of the GIT, which is consistent with its primary digestive and absorptive functions. In addition to daily food and fluid intake (* 1-2 L), the GIT and associated organs secrete about 8 L of fluid per day. Of this, only 100 to 200 mL of stool water is lost per day, indicating efficient absorption of water throughout the tract.

Stomach

After oral ingestion, materials are presented to the stomach, whose primary functions are storage, mixing, and reducing all components to a slurry with the aid of gastric secretions and then emptying these contents in a controlled manner into the upper small intestine (duodenum). All these functions are accomplished by complex neural, muscular, and hormonal processes. Anatomically, the stomach has classically been divided into three

Hernias Along The Tract
Figure 1 Diagrammatic sketch of the gastrointestinal tract (and subdivisions of the small and large intestines) along with associated organs. Source: Modified from Ref. 4.

Table 1 Approximate Lengths of Various Regions of the Human Gastrointestinal Tract

Region Length (m)

Duodenum 0.3

Jejunum 2.4

Ileum 3.6

Large intestine 0.9-1.5

parts: fundus, body, and antrum (or pyloric part), as illustrated in Figure 2 (5). Although there are no sharp distinctions among these regions, the proximal stomach, made up of the fundus and body, serves as a reservoir for ingested material and secretes acid, while the distal region (antrum), which secretes gastrin, is the major site of mixing motions and acts as a pump to accomplish gastric emptying. The fundus and body regions of the stomach have relatively little tone in their muscular wall and, as a result, can distend outward to accommodate a meal of up to 1 L.

A common anatomical feature of the entire GIT is its four concentric layers. Beginning with the luminal (i.e., inner or absorbing) surface these are the mucosa, submucosa, muscularis mucosa, and serosa. The three outer layers are similar throughout most of the tract; however, the mucosa has distinctive structural and functional characteristics. The mucosal surface of the stomach is lined by an epithelial layer of columnar cells, the surface mucous cells, which secrete mucous (mucopolysaccharides) that protects the epithelial surface from acid, enzymes, and pathogens. Covering the epithelial cell surface is a layer of mucous 1.0 to 1.5 mm thick. Along this surface are many tubular invaginations, referred to as gastric pits, at the bottom of which are found specialized gastric secretory cells. These secretory (parietal) cells form part of an

pyloric antrum

Figure 2 Diagrammatic sketch of the stomach and anatomical regions. Source: Modified from Ref. 5.

pyloric antrum

Figure 2 Diagrammatic sketch of the stomach and anatomical regions. Source: Modified from Ref. 5.

extensive network of gastric glands, which produce and secrete about 2 L of gastric fluid daily. The epithelial cells of the gastric mucosa represent one of the most rapidly proliferating epithelial tissues, being shed by the normal stomach at the rate of about a half-million cells per minute. As a result, the surface epithelial layer is renewed every one to three days.

The next region, the muscularis mucosa, consists of an inner circular and an outer longitudinal layer of smooth muscle. This area is responsible for the muscular contractions of the stomach wall needed to accommodate a meal by stretching and for the mixing and propulsive movements of gastric contents. An area known as the lamina propria lies below the muscularis mucosa and contains a variety of tissue types, including connective and smooth muscles, nerve fibers, and the blood and lymph vessels. It is the blood flow to this region and to the muscularis mucosa that delivers nutrients to the gastric mucosa. The major vessels providing a vascular supply to the GIT are the celiac and the inferior and superior mesenteric arteries. Venous return from the GIT is through the splenic and the inferior and superior mesenteric veins. The outermost region of the stomach wall provides structural support for the organ.

Small Intestine

The small intestine has the shape of a convoluted tube and represents the major length of the GIT. The small intestine, comprising the duodenum, jejunum, and ileum, has a unique surface structure, making it ideally suited for its primary role of digestion and absorption. The most important structural aspect of the small intestine is the means by which it greatly increases its effective luminal surface area. The initial increase in surface area, compared with the area of a smooth cylinder, is due to the projection within the lumen of folds of mucosa, referred to as the folds of Kerckring. Lining the entire epithelial surface are fingerlike projections, the villi, extending into the lumen. These villi range in length from 0.5 to 1.5 mm, and it has been estimated that there are about 10 to 40 villi/mm2 of mucosal surface. Projecting from the villi surface are fine structures, the microvilli (average length 1 mm), which represent the final large increase in the surface area of the small intestine. There are approximately 600 microvilli protruding from each absorptive cell lining the villi. Relative to the surface of a smooth cylinder, the folds, villi, and microvilli increase the effective surface area by factors of 3, 30, and 600, respectively.

Villi Small Intestine Diagram

Figure 3 (A) Photomicrograph of the human duodenal surface illustrating the projection of villi into the lumen (magnification 75 x). The goblet cells appear as white dots on the villus surface. (B) Photomicrograph of a single human duodenal villus illustrating surface coverage by microvilli and the presence of goblet cells (white areas) (magnification 2400x). (C) Photomicrograph illustrating the microvilli of the small intestine of the dog (magnification 33,000x). Source: From Ref. 6.

Figure 3 (A) Photomicrograph of the human duodenal surface illustrating the projection of villi into the lumen (magnification 75 x). The goblet cells appear as white dots on the villus surface. (B) Photomicrograph of a single human duodenal villus illustrating surface coverage by microvilli and the presence of goblet cells (white areas) (magnification 2400x). (C) Photomicrograph illustrating the microvilli of the small intestine of the dog (magnification 33,000x). Source: From Ref. 6.

Villi Diagram Black And White
Figure 4 Diagrammatic sketch of the small intestine illustrating the projection of the villi into the lumen (left) and the anatomic features of a single villus (right). Source: Modified from Ref. 4 (see p. 439).

The resulting area represents a surface equal to about two-thirds of a regulation tennis court! These structural features are clearly indicated in the photomicrographs shown in Figure 3. A diagrammatic sketch of the villus is shown in Figure 4.

The mucosa of the small intestine can be divided into three distinct layers. The muscularis mucosa, the deepest layer, consists of a thin sheet of smooth muscle 3 to 10 cells thick and separates the mucosa from the submucosa. The lamina propria, the section between the muscularis mucosa and the intestinal epithelia, represents the subepithelial connective tissue space and together with the surface epithelium forms the villi structure. The lamina propria contains a variety of cell types, including blood and lymph vessels and nerve fibers. Molecules to be absorbed must penetrate into this region to gain access to the bloodstream.

Tract Drug Absorption
Figure 5 Diagrammatic sketch of the intestinal absorptive cell. Source: Modified from Ref. 7.

The third mucosal layer is that lining the entire length of the small intestine and which represents a continuous sheet of epithelial cells. These epithelial cells (or enterocytes) are columnar in shape, and the luminal cell membrane, upon which the microvilli reside, is called the apical cell membrane. Opposite this membrane is the basal (or basolateral) plasma membrane, which is separated from the lamina propria by a basement membrane. A sketch of this cell is shown in Figure 5. The primary function of the villi is absorption.

The microvilli region has also been referred to as the striated or "brush" border. It is in this region where the process of absorption is initiated. In close contact with the microvilli is a coating of fine filaments composed of weakly acidic sulfated mucopolysaccharides. It has been suggested that this region may serve as a relatively impermeable barrier to substances within the gut such as bacteria and other foreign materials. In addition to increasing the effective luminal surface area, the microvilli region appears to be an area of important biochemical activity.

Consistent with the absorptive function of the GIT and, in addition to its large surface area, the enterocyte membrane contains proteins that are responsible for specialized (i.e., nonpassive) transport (influx) of certain molecules. In direct contrast with such processes but consistent with the GIT function as a barrier to the environment, there are also efflux transporters that move absorbed molecules back into the gut lumen. Complementing the efflux transporters is the metabolic activity of the enterocytes reflecting the high concentrations of cytochrome (phase I) and conjugating (phase II) enzymes. These enzymes are known to metabolize many drugs and form the basis for numerous drug-drug and drug-nutrient interactions. These factors are discussed in a later section.

The surface epithelial cells of the small intestine are renewed rapidly and regularly. It takes about two days for the cells of the duodenum to be renewed completely. As a result of its rapid renewal rate, the intestinal epithelium is susceptible to various factors that may influence proliferation. Exposure of the intestine to ionizing radiation and cytotoxic drugs (such as folic acid antagonists and colchicine) reduce the cell renewal rate.

Large Intestine

The large intestine, often referred to as the colon, has two primary functions: the absorption of water and electrolytes and the storage and elimination of fecal material. The large intestine, which has a greater diameter than the small intestine (*6 cm), is connected to the latter at the ileocecal junction. The wall of the ileum at this point has a thickened muscular coat called the ileocecal sphincter, which forms the ileocecal valve, whose principal function is to prevent backflow of fecal material from the colon into the small intestine. From a functional point of view the large intestine may be divided into two parts. The proximal half, concerned primarily with absorption, includes the cecum, ascending colon, and portions of the transverse colon. The distal half, concerned with storage and mass movement of fecal matter, includes part of the transverse and descending colon, the rectum, and anal regions, terminating at the internal anal sphincter (Fig. 1).

In humans, the large intestine usually receives about 500 mL of fluid-like food material (chyme) per day. As this material moves distally through the large intestine, water is absorbed, producing a viscous and finally a solid mass of matter. Because of efficient water absorption, of the 500 mL normally reaching the large intestine, approximately 80 mL are eliminated from the gut as fecal material.

Structurally, the large intestine is similar to the small intestine, although the luminal surface epithelium of the former lacks villi. The muscularis mucosa, as in the small intestine, consists of inner circular and outer longitudinal layers. Figure 6 (8) illustrates a photomicrograph and diagrammatic sketches of this region.

Pathways of Drug Absorption

Once a drug molecule is in solution, it has the potential to be absorbed. Whether or not it is in a form available for absorption depends on the physicochemical characteristics of the drug (i.e., its inherent absorbability) and the characteristics of its immediate environment (e.g., pH, the presence of interacting materials, and the local properties of the absorbing membrane). Assuming that there are no interfering substances present to impede absorption, the drug molecule must come in contact with the absorbing membrane. To accomplish this, the drug molecule must diffuse from the gastrointestinal (GI) fluids to the membrane surface. The most appropriate definition of drug absorption is the penetration of the drug across the intestinal "membrane" and the appearance of the unchanged form in the blood draining the GIT. The latter blood flow will drain into the portal circulation on the way to the liver. A clear distinction must be made between absorbed drug and bioavailable drug. The former was defined above; the latter refers to the appearance of unaltered drug in the systemic circulation (i.e., beyond the liver). There are two important points to this definition. First, it is often assumed that drug disappearance from the GI fluids represents absorption. This is true only if disappearance from the gut represents appearance in the blood stream. This may not be the case, for example, if the drug degrades in GI fluids or if it is metabolized within the intestinal cells. Second, the term intestinal membrane is rather misleading, since this membrane is not a unicellular structure but a number of unicellular membranes parallel to one another. In fact, relative to the molecular size of most drug molecules, the compound must diffuse a considerable distance. Thus, for a drug molecule to reach the blood, it must penetrate the mucous layer and brush border covering the GI lumen, the apical cell surface, the fluids within this cell, the basal membrane, the basement membrane, the tissue region of the lamina propria, the external capillary membrane, the cytoplasm of the capillary cell, and finally, the inner

Drug Absorption

Figure 6 (A) Scanning electron micrograph of the luminal surface of the large intestine (transverse colon; magnification 60x). (B) Schematic diagram showing a longitudinal cross-section of the large intestine. (C) Enlargement of cross-section shown in (B). Source: Part A from Ref. 6 (see p. 135) and parts B and C modified from Ref. 8.

Figure 6 (A) Scanning electron micrograph of the luminal surface of the large intestine (transverse colon; magnification 60x). (B) Schematic diagram showing a longitudinal cross-section of the large intestine. (C) Enlargement of cross-section shown in (B). Source: Part A from Ref. 6 (see p. 135) and parts B and C modified from Ref. 8.

capillary membrane. Therefore, when the expression "intestinal membrane" is used, we are discussing a barrier to absorption consisting of several distinct unicellular membranes and fluid regions bounded by these membranes. Throughout this chapter the term intestinal membrane will be used in that sense.

For a drug molecule to be absorbed from the GIT and gain access to the portal circulation (on its way to the liver), it must effectively penetrate all the regions of the intestine just cited. There are primarily three factors governing this absorption process once a drug is in solution: the physicochemical characteristics of the molecule, the properties and components of the GI fluids, and the nature of the absorbing membrane. Although penetration of the intestinal membrane is obviously the first part of absorption, the factors controlling penetration are discussed in the following section. At this point, assume that the drug molecule has penetrated most of the barriers in the intestine and has reached the lamina propria region. Once in this region the drug may either diffuse through the blood capillary membrane and be carried away in the bloodstream or penetrate the central lacteal and reach the lymph. These functional units of the villi are illustrated in Figure 4. Most drugs reach the systemic circulation via the bloodstream of the capillary network in the villi. The primary reason for this route being dominant over lymphatic penetration is the fact that the villi are highly and rapidly perfused by the bloodstream. Blood flow to the GIT in humans is approximately 500 to 1000 times greater than lymph flow. Thus, although the lymphatic system is a potential route for drug absorption from the intestine, under normal circumstances it will account for only a small fraction of the total amount absorbed. The major exception to this rule will be drugs (and environmental toxicants, such as insecticides) that have extremely large oil/water partition coefficients (Ko/w greater than about 105 or log partition of 5). By increasing lymph flow or, alternatively, reducing blood flow, drug absorption via the lymphatic system may become more important. The capillary and lymphatic vessels are rather permeable to most low-molecular-weight and lipid-soluble compounds. The capillary membrane, however, represents a more substantial barrier than the central lacteal to the penetration of very large molecules or combinations of molecules as a result of frequent separations of cells along the lacteal surface. The lymphatic route of movement is important, for example, for the absorption of triglycerides or emulsified fats in the form of chylomicrons, which are rather large (* 0.5 mm in diameter). A recent study has concluded that effective lymphatic absorption of a drug depends not only on Ko/w but also on the ability to partition into chylomicrons and long-chain triglycerides (9).

PHYSICOCHEMICAL FACTORS GOVERNING DRUG ABSORPTION Oil/Water Partition Coefficient and Chemical Structure

As a result of extensive experimentation done in the early 1900s, it has been found that the primary physicochemical properties of a drug influencing its passive absorption into and across biological membranes are its Ko/w, extent of ionization in biological fluids determined by its pKa value and pH of the fluid in which it is dissolved, and its molecular weight or volume. Passive absorption refers to a first-order kinetic process not having any membrane involvement (i.e., no energy is required or expended for transport to occur). The fact that these variables govern drug absorption is a direct reflection of the nature of biological membranes. The cell surface of biological membranes (including those lining the entire GIT) is lipid in nature; as a result, one may view penetration into the intestinal cells as a competition for drug molecules between the aqueous environment on one hand and the lipid-like materials of the membrane on the other. To a large extent, then, the principles of solution chemistry and the molecular attractive forces to which the drug molecules are exposed will govern movement from an aqueous phase to the lipid-like phase of the membrane.

At the turn of the last century, Overton examined the osmotic behavior of the frog sartorius muscle soaked in a buffer solution containing various dissolved organic compounds. He reasoned that, if the solute entered the tissue, the weight of the muscle would remain essentially unchanged, whereas, loss of weight would indicate an osmotic withdrawal of fluid and hence impermeability to the solute in solution. He noted that, in general, the tissue was most readily penetrated by lipid-soluble compounds and poorly penetrated by lipid-insoluble substances. Overton was one of the first investigators to illustrate that compounds penetrate cells in the same relative order as their Ko/w, suggesting the lipid-like nature of cell membranes. Using animal or plant cells, other workers provided data in support of Overton's observations. The only exception to this general rule was the observation that very small molecules penetrate cell membranes faster than would be expected based on their Ko/w values. To explain the rapid penetration of these small molecules (e.g., urea, methanol, formamide), it was suggested that cell membranes, although lipid in nature, were not continuous but interrupted by small water-filled channels or "pores"; such membranes are best described as being lipid-sieve membranes. As a result, one could imagine lipid-soluble molecules readily penetrating the lipid regions of the membrane while small water-soluble molecules pass through the aqueous pores. Fordtran et al. (10) estimated the effective pore radius to be 7 to 8.5 and 3 to 3.8 A in human jejunum and ileum, respectively. There may be a continuous distribution of pore sizes, a smaller fraction of larger ones and a greater fraction of smaller pores.

Our knowledge of biological membrane ultrastructure is the result of rapid advances in instrumentation. Although some controversy remains over the most correct biological membrane model, the concept of membrane structure presented by Davson and Danielli of a lipid bilayer is perhaps the one best accepted (11,12). The most current version of that basic model is illustrated in Figure 7 and is referred to as the "fluid mosaic" model of membrane structure (13). That model is consistent with what we have learned about the existence of specific ion channels and receptors within and along surface membranes.

Table 2 summarizes some literature data supporting the general dependence of the rate of absorption on Ko/w, as measured in the rat intestine (14,15). As with numerous other examples, as Ko/w increases, the rate of absorption increases. However, note that this is seldom a simple linear relationship. For example, secobarbital has a value for absorption that is about three-times that of barbital; however, Ko/w differs by 70-fold. One very extensive study (16-18) has examined in depth the physicochemical factors governing nonelectrolyte permeability for several hundred compounds. This study employed an in vitro rabbit gallbladder preparation, an organ whose mucosal surface is lined by epithelial cells. The method used to assess solute permeability is based upon

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