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Gastrointestinal Tract

The gastrointestinal tract (the major portion of the alimentary canal) can be viewed as a tube going through the body.  Its contents are considered exterior to the body until absorbed. Salivary glands, liver, and the pancreas are considered accessory glands of the GI tract as they have ducts entering the GI tract and secrete enzymes and other substances.  For foreign substances to enter the body, they must pass through the gastrointestinal mucosa, crossing several membranes before entering the blood stream.

Substances must be absorbed from the gastrointestinal tract in order to exert a systemic toxic effect, although local gastrointestinal damage may occur.  Absorption can occur at any place along the entire gastrointestinal tract.  However, the degree of absorption is strongly site-dependent.

V. C. Scanlon and T. Sanders, Essentials of Anatomy and Physiology, 2nd edition. F. A. Davis, 1995.

Three main factors affect absorption within the various sites of the gastrointestinal tract:

type of cells at the specific site

period of time that the substance remains at the site

pH of stomach or intestinal contents at the site

Under normal conditions, xenobiotics are poorly absorbed within the mouth and esophagus, due mainly to the very short time that a substance resides within these portions of the gastrointestinal tract.  There are some notable exceptions.  For example, nicotine readily penetrates the mouth mucosa.  Nitroglycerin is placed under the tongue (sublingual) for immediate absorption and treatment of heart conditions.  The sublingual mucosa under the tongue and in some other areas of the mouth is thin and highly vascularized so that some substances will be rapidly absorbed.

The stomach, which has high acidity (pH 1-3), is a significant site for absorption of weak organic acids, which exist in a diffusible, nonionized and lipid-soluble form.  In contrast, weak bases will be highly ionized and therefore poorly absorbed.  The acidic stomach may chemically break down some substances.  For this reason those substances must be administered in gelatin capsules or coated tablets, which can pass through the stomach into the intestine before they dissolve and release their contents.

Another determinant that affects the amount of a substance that will be absorbed in the stomach is the presence of food in the stomach.  Food ingested at the same time as the xenobiotic may result in a considerable difference in absorption of the xenobiotic.  For example, the LD50 for Dimethline (a respiratory stimulant) in rats is 30 mg/kg when ingested along with food, but only 12 mg/kg when it is administered to fasting rats.

The greatest absorption of chemicals, as with nutrients, takes place in the intestine, particularly in the small intestine.  The intestine has a large surface area consisting of outward projections of the thin (one-cell thick) mucosa into the lumen of the intestine (the villi).  This large surface area facilitates diffusion of substances across the cell membranes of the intestinal mucosa.

Since the pH is near neutral (pH 5-8), both weak bases and weak acids are nonionized and are usually readily absorbed by passive diffusion.  Lipid soluble, small molecules effectively enter the body from the intestine by passive diffusion.

V. C. Scanlon and T. Sanders, Essentials of Anatomy and Physiology, 2nd edition. F. A. Davis, 1995.

In addition to passive diffusion, facilitated and active transport mechanisms exist to move certain substances across the intestinal cells into the body, including essential nutrients, such as glucose, amino acids and calcium.  Strong acids, strong bases, large molecules, and metals are also transported by these mechanisms, including some important toxins.  For example, lead, thallium, and paraquat (herbicide) are toxins that are transported across the intestinal wall by active transport systems.

The high degree of absorption of ingested xenobiotics is also due to the slow movement of substances through the intestinal tract.  This slow passage increases the length of time that a compound is available for absorption at the intestinal membrane barrier.

Intestinal microflora and gastrointestinal enzymes can affect the toxicity of ingested substances.  Some ingested substances may be only poorly absorbed but they may be biotransformed within the gastrointestinal tract.  In some cases, their biotransformed products may be absorbed and be more toxic than the ingested substance.  An important example is the formation of carcinogenic nitrosamines from non-carcinogenic amines by intestinal flora.

Very little absorption takes place in the colon and rectum.  As a general rule, if a xenobiotic has not been absorbed after passing through the stomach or small intestine, very little further absorption will occur.  However, there are some exceptions, as some medicines may be administered as rectal suppositories with significant absorption.  An example, is Anusol (hydrocortisone preparation) used for treatment of local inflammation which is partially absorbed (about 25%).

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