The human GIT

2.4.1.1 Anatomy and function

The human GIT extends from the oral cavity to the anus. It is divided into the following different specialized compartments: oral cavity, esophagus, stomach, small intestine and large intestine. The outcomes of this compartmentalization are different physiological and chemical conditions along the GIT (Rehner and Daniel, 2002).

Figure 2-4 gives a detailed schematic overview of the GIT structure.

2.4.1.2 Upper GIT

Once food has been ingested into the oral cavity its particle size will be reduced through the process of chewing and afterwards reaches the esophagus by swallowing. Here the bolus is transported via peristaltic contractions into the stomach. Hereby salivary secretion in the oral cavity facilitates the lubrication and stirs food with two digestive enzymes: α-amylase (cleaves internal α-1,4-glycoside bonds present in starch) and lingual lipase (hydrolysis of dietary lipid) (Johnson, 2007; Weisbrodt, 2007).

Figure 2-4: Schematic detailed overview of the human GIT (copied from (Corwin, 2008).

2.4.1.2.1 Stomach

In the stomach the bolus is stirred with gastric juice and particle size is decreased again. The major constituents of gastric juice are pepsin, mucus, hydrogen ions and the intrinsic factor. Despite the activity of saliva enzymes and the proteolytic activity of pepsin in the stomach, gastric digestion plays only a minor role in the degradation of macromolecules (Rehner and Daniel, 2002). In a fasted state, the pH of gastric fluid ranges from 1 to 3.5 and can rise in fed state up to 4.5 and higher (Fallingborg, 1999; Rehner and Daniel, 2002) (see Figure 2-5).

Figure 2-5: Changing of gastric pH (A) and gastric emptying rate (B), after consumption of a meal (400 mL, half viscous, pH 6, 40% carbohydrates, 40%

fat, 20% protein). Modified according to (Malagelada et al., 1976).

Gastric emptying is accomplished by coordinated contractile activity of the stomach, pylorus and proximal small intestine (Weisbrodt, 2007). Solid food passes the stomach only after a reduction of its particle size which requires an adequate resistance time of such foods in the stomach. Only particles with 1 mm³ or less are easily emptied by gastric motility, whereas liquids passes the stomach immediately (Weisbrodt, 2007) (see Figure 2-5).

Furthermore, the chemical composition of foods affects the rate of gastric emptying.

For instance, foods that are high in lipids, H⁺ or that differ considerably from isotonicity pass the stomach at a slower rate than observed for near-isotonic saline solutions (Rehner and Daniel, 2002; Weisbrodt, 2007). Receptors in the upper small intestine regulate the gastric emptying. These receptors respond to physical properties (osmotic pressure) and chemical composition (H⁺, lipids) of the bolus (Weisbrodt, 2007). In addition to the type of meal, other factors such as body position, emotional state, and activity (exercise) can affect the rate of gastric emptying (Chereson, 1996).

Thereupon the motility is influencing the amount of bolus reaching the small intestine.

More specifically, in a study which observed the gastric emptying time after consumption of different breakfasts, the following emptying times were reported: high carbohydrate 120 ± 75 min; high fat and protein content 580 ± 375 min; and 150 mL water 45 ± 110 min (measured by a radio capsule) (Zimmermann and Leitold, 1992).

2.4.1.2.2 Small intestine

Anatomically the small intestine extends from the gastroduodenal junction (pylorus) to the duodenum, followed by the jejunum to the ileum. It ends at the ileocecal junction (Figure 2-4). In the duodenum, pancreas and gallbladder effluent are excreted to the chyme. As a consequence of the hydrogen carbonate content of pancreas secretion and duodenal gland efflux, the pH is raised in the aboral direction of the small intestine (pH in fed state: duodenum 5.4, jejunum 5.2 – 6.0, ileum 7.5) (Hörter and Dressman, 2001; Rehner and Daniel, 2002).

Furthermore, pancreas effluent contains important enzymes for digestion, especially for carbohydrate digestion, proteolysis and lipolysis. The major function of the gallbladder is to emulsify the fat in the chyme by bile acids. These acids are produced by hepatocytes in the liver and are stored within the gallbladder until excretion. So the liver and gallbladder are also important for digestion because bile acids increase the absorption of fats and consequently high lipophilic drugs (El-Kattan and Varma, 2012). Additionally, once molecules are absorbed in the small intestine they can be transformed in the liver and excreted via the gallbladder into small intestine (enterohepatic circulation). More specifically, the liver plays a major role in detoxification and excretion of xenobiotics. Absorbed molecules undergo a biotransformation and can be excreted in the liver as well as in the small intestine itself which can lead to a limited oral bioavailability (see chapter 2.6.2.4) (Dietrich et al., 2003; El-Kattan and Varma, 2012).

The motility of the small intestine homogenizes the chyme with digestive fluids and enzymes, facilitating contact with the intestinal mucosa of the entire chyme and propulsion in an aboral direction (Weisbrodt, 2007). Thus, the small intestine is the part of the GIT where most digestion and absorption take place. For this, the small intestine has a specialized mucosa in order to maximize the intestinal absorptive surface area (Rehner and Daniel, 2002) with circular folds, villi and microvilli at the enterocyte. These structures create an absorptive surface area of 300 to 400 m² in the small intestine. In Figure 2-6 the anatomy and different tissue layers of the small intestine are shown. The villi and the tunica mucosa are situated at the luminal side of the small intestine, followed by the thin muscle layer of muscularis mucosa. The tela submucosa, the longitudinal and circular muscle layers of lamina muscularis follow which regulate the motility of the small intestine. The tunica serosa (a tissue nerved with blood vessels) completes the small intestine wall at the serosal side.

Besides the enterocytes, other specialized cells are occurring in the small intestine such as paneth and microfold cells.

Figure 2-6: Anatomy and surface enlarging factors of the small intestine on the left and architecture of the different tissue layers with vasculature on the right.

According to (Rehner and Daniel, 2002).

Furthermore, the small intestinal microbiota is also involved in the process of digestion, as shown by Knaup et al. investigating the degradation of several quercetin glycosides in the ileal fluid (Knaup et al., 2007). Colonization of microbiota in the small intestine varies within the different parts and increases from the duodenum with 10³ cfu*mL^-1 to the jejunum and ileum with 10⁴ – 10⁸ cfu*mL^-1 (Blaut and Clavel, 2007) .

The total transit time of chyme in the small intestine varies from 2.8 up to 6.3 hours (Ibekwe et al., 2006). Hereby the flow from the small intestine to the large intestine is partly regulated by the ileocecal junction at the end of the small intestine (Weisbrodt, 2007).

2.4.1.3 Large intestine

The large intestine can anatomically be divided into the cecum, ascending-, transverse-, and descending colon and the rectum (Figure 2-4). The major function of the large intestine is to absorb water and electrolytes. In total the absorptive surface area of the large intestine is not important. Typical surface anatomy present in the small intestine such as villi and microvilli cannot be observed (Rehner and Daniel, 2002).

Because of the high amount of microbiota in the colon (10⁹ – 10¹² cfu*mL^-1(Blaut and Clavel, 2007)) it is a compartment where chyme compounds, which were not absorbed in the upper GIT, are fermented forming short chain fatty acids such as butyrate from non absorbed carbohydrates. The metabolic activity of these bacterial microflora can play a major role in liberation of drugs by hydrolysis, dehydroxylation, deamidation, decarboxylation, and reduction of acid groups (see chapter 2.6.2.1) (El-Kattan and Varma, 2012). The pHs of the colon are: cecum 5.7; ascending colon 5.6;

transverse colon 5.7 and descending colon 6.6 (Fallingborg, 1999). Contractions organize the aboral movement of contents via the colon and evacuation of feces (Weisbrodt, 2007). A colonic transit time of 25 up to 30 hours is reported (Silbernagl and Despopoulos, 2003).

2.4.1.4 Unstirred water layer

Adjacent to the intestinal membrane an unstirred water layer is present with a thickness of 25 µm in humans. The effect of this polar unstirred water layer is insignificant on the extent of absorption, even on high lipophilic molecules (Chiou, 1994; El-Kattan and Varma, 2012).