Please remember these concepts:

1. Many processes can be at equilibrium.   But with changes in condition - concentration, temperature -  the system will no longer be at equilibrium and will adjust to try to get there again.
2. The equilibrium concentrations of H₃O⁺ and OH^- are vanishingly small in pure water. 
3. A weak acid or a weak base drug, in water, will disassociate to some extent.  The pH of the drug solution  will depend upon the pK_a.
4. Buffers stabilize pH.  This stabilized acidity determines the form of drug disassociation in systems.  The Henderson-Hasselbach equation conveniently handles drug ionization questions for buffered systems like the body.

And finally, we're ready to take a look at what happens in a biological system when a drug dissolves in the gastrointestinal fluid and is transported across biological membranes.

We can divide the portions of the gastrointestinal tract based on the organs of digestion along the alimentary canal. Each portion along the digestive tract has a different pH. This would equate to buffer solutions of varying hydronium ion concentrations in which a salt is dissolved.

A brief review of gastrointestinal anatomy and physiology may provide some insight into the composition of the fluids found at each section. 

The first section of the alimentary canal that a drug comes in contact with is the oral cavity. Seldom does the dosage form remain in this cavity long enough for drug absorption to take place, unless the drug is administered bucally or sublingually. The absorption mechanism under the tongue is different than that in the GI tract.  Materials, absorb directly into the circulatory system under the tongue;   they do not pass to the liver and then out into systemic circulation.  A complete discussion of sublingual absorption is beyond the scope of this discussion, but many drugs are intended for administration in this fashion. 

Usually, the tablet, capsule, solution or suspension administered orally finds its way pretty quickly to the stomach, passing through the esophagus. Drug absorption does not normally occur in the esophagus, because the transport time is rapid.

Our stomachs are vessels with .5-1 liter capacity.   The contents of the stomach include hydrochloric acid, pepsinogen, and mucus. The pH of the stomach in a normal, healthy human is in the 1-3 range. There are many purposes for the high acidity found in the stomach. One of the main functions of the high acid content is to destroy bacteria that are ingested. Few bacteria can survive in an environment with a pH of 1 to 3! Some do, though, because on an impenetrable outer coat that can resist acid breakdown. Another purpose for such a low pH is that high acidity is required to activate pepsinogen. Pepsinogen is the enzyme that initiates the digestion and breakdown of proteins that are ingested.  The other major component of gastric fluid is mucus. Mucus provides protection to the stomach lining from the high acid content. Gastric pH varies from time to time. Gastric acid is secreted in anticipation of a meal, to prepare for digestion. Gastric pH decreases as a result of acid secretion, and, after a heavy meal, blood pH correspondingly increases, particularly in those segments of the circulatory system associated with supplying the gastrointestinal tract. This increase in blood pH is known as the "alkaline tide", and is caused by bicarbonate ions that are secreted into extracellular fluid of the stomach, then into venous blood.

Further down the alimentary canal is the small intestine, the first part of which is the duodenum. The pH of the duodenum is 6 to 6.5. The majority of nutrients, vitamins, and drugs are absorbed in this 6 inch area of the gastrointestinal tract. In addition to water, mucus, and electrolytes, secretions from the liver and pancreas join secretions from the intestinal mucosa to facilitate digestion and absorption. The anatomy of the small intestines is such that a very large surface area that provides better absorption is available. The lining of the small intestines is composed of many villi, or finger like projections, which extend even more as projections called the brush border. The area is highly perfused with blood. These factors contribute to a very high surface area, increasing the likelihood of drug absorption taking place, if the ionization criterion is met. The pH can reach 7 to 8 in this area.

Further along the small intestine, beyond the duodenum, lies the jejunum and ileum.  These sections of the small intestine lack the high surface area of the duodenum and only small amounts of absorption across the lipid membranes occurs in this section of the small intestine.  As we get further away from the stomach, the pH rises to about 7.5 in this region.

And the final organ of the digestive tract is the large intestine, which includes the colon and rectum. The large intestine is the site for water resorption and the production of feces. Seldom does drug absorption take place in this region. The pH of the large intestine is 5.5-7, and like the buccal area, blood that drains the rectum is not first transported to the liver. So, absorption that takes place in the rectum (from rectal suppositories and enemas) goes into the systemic circulation without biotransformation that takes place due to liver enzymes.

to Ionization within the Stomach

14a. Absorption in the Stomach
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