Physiological factors influencing oral drug absorption

The gastrointestinal tract is complex. Fig. 19.1 outlines some of the main structures involved in, and key physiological parameters that affect oral drug absorption.

In order to gain an insight into the numerous factors that can potentially influence the rate and extent of drug absorption into the systemic circulation,
a schematic illustration of the steps involved in the release and absorption of a drug from a tablet dosage form is presented in Fig. 19.2.

 

It can be seen from this that the rate and extent of appearance of intact drug in the systemic circulation depend on a succession of kinetic processes.

The slowest step in this series, which is the ratelimiting step, controls the overall rate and extent of appearance of intact drug in the systemic circulation.

The rate-limiting step will vary from drug to drug. For a drug which has a very poor aqueous solubility, the rate at which it dissolves in the gastrointestinal fluids is often the slowest of all the steps, and the bioavailability of that drug is said to be dissolution-rate limited.

In contrast, for a drug that has a high aqueous solubility, its dissolution will be rapid, and the rate at which the drug crosses the gastrointestinal membrane may be the rate-limiting step, termed permeability limited.

Other potential rate-limiting steps include the rate of drug release from the dosage form (this can be by design, in the case of controlled-release dosage
forms), the rate at which the stomach empties the drug into the small intestine, the rate at which the drug is metabolized by enzymes in the intestinal mucosal cells during its passage through them into the mesenteric blood vessels, and the rate of metabolism of the drug during its initial passage through the liver, often termed the ‘first-pass’ effect.

Physiology of the gastrointestinal tract

The gastrointestinal tract is a muscular tube, approximately 6 m in length with varying diameters. It stretches from the mouth to the anus and consists of four main anatomical areas; the oesophagus, the stomach, the small intestine and the large intestine, or colon. The luminal surface of the tube is not smooth
but very rough, thereby increasing the surface area for absorption.

The wall of the gastrointestinal tract is essentially similar in structure along its length, consisting of four principal histological layers (Fig. 19.3):

  1. The serosa, which is an outer layer of epithelium with supporting connective tissues which are continuous with the peritoneum.
  2. The muscularis externa, which contains three layers of smooth muscle tissue, a thinner outer
    layer, which is longitudinal in orientation, and two inner layers, whose fibres are oriented in a
    circular pattern. Contractions of these muscles provide the forces for movement of gastrointestinal tract contents and physical breakdown of food.
  3. The submucosa, which is a connective tissue layer containing some secretory tissue and
    which is richly supplied with blood and lymphatic vessels. A network of nerve cells, known as the submucous plexus, is also located in this layer.
  4. The mucosa, which is essentially composed of three layers: the muscularis mucosae, which can
    alter the local conformation of the mucosa, a layer of connective tissue known as the lamina propria, and the epithelium.

The majority of the gastrointestinal epithelium is covered by a layer or layers of mucus. This is a viscoelastic translucent aqueous gel that is secreted
throughout the gastrointestinal tract, acting as a protective layer and a mechanical barrier.

Mucus is a constantly changing mix of many secretions and exfoliated epithelial cells. It has a large water component (~95%). Its other primary components,
which are responsible for its physical and functional properties, are large glycosylated proteins called mucins.

Mucins consist of a protein backbone
approximately 800 amino acids long and oligosaccharide side chains that are typically up to 18 residues
in length. The mucous layer ranges in thickness from 5 µm to 500 µm along the length of the gastrointestinal
tract, with average values of approximately 80 µm.

Mucus is constantly being removed from the luminal surface of the gastrointestinal tract through
abrasion and acidic and/or enzymatic breakdown, and it is continually replaced from beneath.

The turnover time has been estimated at 4 to 5 hours, but this may well be an underestimate and is liable to vary
along the length of the tract.

Oesophagus

The mouth is the point of entry for most drugs (so-called peroral – via the mouth – administration).

At this point, contact with the oral mucosa is usually brief. Linking the oral cavity to the stomach is the oesophagus.

The oesophagus is composed of a thick
muscular layer approximately 250 mm long and 20 mm in diameter. It joins the stomach at the gastro-oesophageal junction, or cardiac orifice, as it is sometimes known.

The oesophagus, apart from the lowest 20 mm, which is similar to the gastric mucosa, contains a well-differentiated squamous epithelium of nonproliferative cells.

Epithelial cell function is mainly
protective; salivary glands in the mouth secrete mucins into the narrow lumen to lubricate food and protect the lower part of the oesophagus from gastric acid.

The pH of the oesophageal lumen is usually between 5 and 6.
Materials are moved down the oesophagus by the act of swallowing.

After swallowing, a single peristaltic
wave of contraction, its amplitude linked to the size of the material being swallowed, passes down the
length of the oesophagus at a rate of 20 mm s−1 to 60 m s−1, speeding up as it progresses.

When swallowing is repeated in quick succession, the subsequent swallows interrupt the initial peristaltic wave and only the final wave proceeds down the length of the oesophagus to the gastrointestinal junction, carrying material within the lumen with it.

Secondary peristaltic waves occur involuntarily in response to any distension of the oesophagus and serve to move sticky lumps of material or refluxed material to the stomach.

In the upright position, the transit of materials through the oesophagus is assisted by gravity. The oesophageal
transit of dosage forms is extremely rapid, usually of the order of 10 to 14 seconds.

Stomach

The next part of the gastrointestinal tract to be encountered by both food and pharmaceuticals is the stomach. The two major functions of the stomach
are:

  •  To act as a temporary reservoir for ingested food and to deliver it to the duodenum at a controlled rate.
  •  To reduce ingested solids to a uniform creamy consistency, known as chyme, by the action of
    acid and enzymatic digestion. This enables better contact of the ingested material with the mucous membrane of the intestines and thereby facilitates absorption.

Another, perhaps less obvious, function of the stomach is its protective role in reducing the risk of noxious agents reaching the intestine. The stomach is the most dilated part of the gastrointestinal tract and is situated between the lower end of the oesophagus and the small intestine. Its opening to the duodenum is controlled by the pyloric sphincter. The stomach can be divided into four anatomical regions (Fig. 19.4): the fundus, the body, the antrum and the pylorus.

The stomach has a capacity of approximately 1.5 L, although under fasting conditions it usually contains no more than 50 mL of fluid, which is mostly gastric secretions. These include:

  • Hydrochloric acid secreted by the parietal cells, which maintains the pH of the stomach between 1 and 3.5 in the fasted state.
  • The hormone gastrin, which itself is a potent stimulator of gastric acid production and pepsinogen and is released by the G cells in the
    stomach. The release of gastrin is stimulated by peptides, amino acids and distension of the stomach and causes increased gastric motility.
  • Pepsins, which are secreted by the chief cells in the form of its precursor pepsinogen. Pepsins
    are peptidases which break down proteins to peptides at low pH. Above pH 5, pepsin is denatured.
  • Mucus, which is secreted by the surface mucosal cells and lines the gastric mucosa. In the stomach the mucus protects the gastric mucosa from autodigestion by the pepsin–acid combination.

Very little drug absorption occurs in the stomach owing to its small surface area compared to the small intestine. The rate of gastric emptying can be a controlling factor in the onset of drug absorption from the major absorptive site, the small intestine.

Small intestine

The small intestine is the longest (4 m to 5 m) and most convoluted part of the gastrointestinal tract, extending from the pyloric sphincter of the stomach
to the ileocaecal junction, where it joins the large intestine. It is approximately 25 mm to 30 mm in diameter. Its main functions are:

  • digestion – the process of enzymatic digestion, which began in the stomach, is completed in the small intestine; and
  • absorption – the small intestine is the region where most nutrients and other materials are absorbed.

The small intestine is divided into the duodenum, which is 200 mm to 300 mm in length, the jejunum, which is approximately 2 m in length, and the ileum, which is approximately 3 m in length.

The wall of the small intestine has a rich network of both blood and lymphatic vessels. The gastrointestinal circulation is the largest systemic regional vasculature, and nearly one-third of the cardiac output flows through the gastrointestinal viscera. The blood vessels of the small intestine receive blood from the superior mesenteric artery via branched arterioles.

The blood leaving the small intestine flows into the hepatic portal vein, which carries it via the liver to the systemic circulation. Drugs that are metabolized
by the liver are degraded before they reach the systemic circulation; this is termed hepatic presystemic
clearance or first-pass metabolism.

The wall of the small intestine also contains lacteals, which contain lymph and are part of the lymphatic system.

The lymphatic system is important
in the absorption of fats from the gastrointestinal tract. In the ileum there are areas of aggregated lymphoid tissue close to the epithelial surface which are known as Peyer’s patches (named after
the 17th-century Swiss anatomist Johann Peyer).

These cells play a key role in the immune response as they transport macromolecules and are involved
in antigen uptake. The surface area of the small intestine is increased
enormously, by approximately 600 times that of a simple cylinder, to approximately 200 m2 in an adult,
by several adaptations which make the small intestine such a good absorption site:

  • Folds of Kerckring – these are submucosal folds which extend circularly most of the way around
    the intestine and are particularly well developed in the duodenum and jejunum. They are several
    millimetres in depth.
  • Villi – these have been described as finger-like projections into the lumen (approximately 0.5 mm to 1.5 mm in length and 0.1 mm in
    diameter). They are well supplied with blood vessels. Each villus contains an arteriole, a venule and a blind-ending lymphatic vessel
    (lacteal). The structure of a villus is shown in Fig. 19.5.
  • Microvilli – 600 to 1000 of these brush-like structures (~1 µm in length and 0.1 µm in width) cover each villus, providing the largest
    increase in surface area. These are covered by a fibrous substance known as glycocalyx.

The luminal pH of the small intestine increases to between 6 and 7.5. Sources of secretions that produce these pH values in the small intestine are:

  • Brunner’s glands. These are located in the duodenum and are responsible for the secretion
    of bicarbonate, which neutralizes the acid emptied from the stomach..
  • Intestinal cells. These are present throughout the small intestine and secrete mucus and enzymes. The enzymes, hydrolases and proteases, continue the digestive process.
  • Pancreatic secretions. The pancreas is a large gland that secretes approximately 1 L to 2 L of pancreatic juice per day into the small intestine via a duct. The components of pancreatic juice are sodium bicarbonate and enzymes. The enzymes consist of proteases, principally trypsin, chymotrypsin and carboxypeptidases, which are secreted as inactive precursors or zymogens and are converted to their active forms in the lumen by the enzyme enterokinase. Lipase and amylase are both secreted in their active forms. The bicarbonate component is largely regulated by the pH of chyme delivered into the small intestine from the stomach.
  • Bile. Bile is secreted by hepatocytes in the liver into bile canaliculi, concentrated in the gallbladder and hepatic biliary system by the removal of sodium ions, chloride ions and water, and delivered to the duodenum. Bile is a complex aqueous mixture of organic solutes (bile acids, phospholipids, particularly lecithin, cholesterol and bilirubin) and inorganic compounds (such as the plasma electrolytes sodium and potassium). Bile pigments, the most important of which is bilirubin, are excreted in the faeces but the bile acids are reabsorbed by an active process in the terminal ileum. They are returned to the liver via the hepatic portal vein and, as they have a high hepatic clearance, are resecreted in the bile. This process is known as enterohepatic recirculation. The main functions of the bile are promoting the efficient absorption of dietary fat, such as fatty acids and cholesterol, by aiding its emulsification and micellar solubilization, and the provision of excretory pathways for degradation products.

Colon

The colon is the final major part of the gastrointestinal tract. It stretches from the ileocaecal junction to the anus and makes up approximately the last 1.5 m of the 6 m of the gastrointestinal tract. It is composed of the caecum (~85 mm in length), the ascending colon (~200 mm), the hepatic flexure, the transverse
colon (usually longer than 450 mm), the splenic flexure, the descending colon (~300 mm), the sigmoid colon (~400 mm) and the rectum, as shown
in Fig. 19.6.

The ascending colon and the descending
colon are relatively fixed, as they are attached via the flexures and the caecum. The transverse colon and the sigmoid colon are much more flexible.

The colon, unlike the small intestine, has no specialized villi. However, the microvilli of the absorptive epithelial cells, the presence of crypts and the
irregularly folded mucosae serve to increase the surface area of the colon by 10 to –15 times that of a simple cylinder.

The surface area nevertheless remains approximately l/30 that of the small
intestine.

The main functions of the colon are:

  • The absorption of sodium ions, chloride ions and water from the lumen in exchange for bicarbonate and potassium ions. Thus the colon
    has a significant homeostatic role in the body.
  • The storage and compaction of faeces.

The colon is permanently colonized by an extensive number (approximately 1012 per gram of contents) and variety of bacteria. This large bacterial mass is capable of several metabolic reactions, including hydrolysis of fatty acid esters and the reduction of inactive conjugated drugs to their active form.

The bacteria rely on undigested polysaccharides in the diet and the carbohydrate components of secretions such as mucus for their carbon and energy sources. They degrade the polysaccharides to produce short-chain fatty acids (acetic, propionic and butyric acids), which lower the luminal pH, and the gases hydrogen, carbon dioxide and methane. Thus the pH of the caecum is approximately 6 to 6.5. This increases to approximately 7 to 7.5 towards the distal parts of the colon.

Recently there has been much interest in the exploitation of the enzymes produced by these bacteria with respect to targeted drug delivery to this region of the gastrointestinal tract.

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