GASTROINTESTINAL PHYSIOLOGICAL RESPONSE TO INGESTED FOOD AND LIQUIDS

The anatomy of the GIT has been well characterized by numerous texts and will
not be covered in this chapter. The effects of food, however, on GIT secretions,
motility, and dynamics are integral to understanding how food will affect the pharmacokinetic
parameters mentioned in the previous section. The primary focus of
this section will be to discuss the physiological processes mentioned in the rate of
absorption section.
Gastric Emptying Rate
Arguably, the gastric (stomach) emptying rate (GER) is the most important
parameter that influences the rate of drug absorption from the GIT. Since most of
a drug dose is absorbed in the small intestine, the rate at which the drug is presented
to the small intestine is often the rate-limiting process of drug absorption. Many
factors can influence the GER, including the type and volume of meal ingested, the
emotional state of the patient, the body position of the patient, and coadministered
drugs.1 Table 2.1 eloquently describes how various factors influence gastric emptying
rate. The GER is slower for solids, which need more processing than do liquids
prior to presentation to the small intestine.1,2
Solids
Owing to the primary function of the stomach, the ingestion of food delays the
gastric emptying rate.3 In addition, the magnitude of this decrease in GER is dependent
on the volume and the type of meal ingested (see Table 2.1). High-fat meals
tend to slow the rate of gastric emptying to a greater degree than one rich in
carbohydrates or amino acids. The ingestion of food elevates gastric pH and slows
the longitudinal motility of the stomach to allow food sequestration in the stomach
for processing. Changes in stomach pH that result from food ingestion can produce
significant effects on drug absorption for those drugs whose dissolution is dependent
on low pH. This topic will be covered in the section on Drug Dissolution.
In some instances, food can alter the rate order of drug absorption. The amount
of the vitamin riboflavin absorbed has been studied in fasted and fed subjects.3 In
fasted subjects, riboflavin is absorbed in a zero order fashion. In other words, the
amount of drug absorbed as a function of time will not change regardless of the
magnitude of the dose. In the presence of food, the presentation of riboflavin to
Table 2.1 Circumstances That Influence Gastric Emptying

the absorption site is slowed to the point that absorption occurs at a first order rate.
The presentation of riboflavin was sufficiently slow that the transport carriers were
not saturated. Thus, the amount of drug absorbed increased as the dose increased
(Table 2.2).
Liquids
The ingestion of liquids does not significantly reduce the GER, primarily because
liquids need minimal physiological processing before their presentation into the small
intestine. Recent studies suggest, however, that liquids can indeed slow the GER as
a function of their caloric content.2–3 This theory is supported by data obtained in
various laboratories that investigated whether the use of an acidic beverage, such as
Coca-Cola® or grapefruit juice, may lower the pH of the stomach and thus promote
the dissolution of the weakly basic drugs (e.g., itraconazole and ketoconazole). In
addition, this longer residence time in the stomach may aid in the solvation of poorly
Table 2.2 First Order and Zero Order Absorption as a Function of Food
Presence

soluble, lipophilic drugs such as itraconazole.5–8 Figure 2.4 depicts the benefit of a
delay in gastric emptying as the CMAX and AUC of itraconazole were dramatically
improved by the reduction in gastric emptying rate following ingestion of Coca-
Cola®. At pH values that should have promoted prompt drug dissolution and absorption
(e.g., pH 1–3), the rates of absorption of these drugs, as reflected in TMAX values,
was not enhanced by the acidic beverage.8 To further emphasize the point, Carver
and colleagues lowered the gastric pH using glutamic acid and demonstrated that
the TMAX of itraconazole was unchanged.5 Therefore, the caloric content of the liquid
may be the determining factor in the magnitude of GER reductions.
The volume of fluid also plays a role in the rate of absorption. This was demonstrated
in studies with several antibiotics taken with a small volume of water (e.g.,
20–25 mL) or a large volume of water (e.g., 250–500 mL). Dramatic differences
were observed in the drug concentration vs. time profiles for these drugs simply as
a function of the volume of fluid ingested (Figure 2.5). Thus, patients who take
medications with a large volume of water as opposed to a small volume of water
may exhibit considerably different onset, duration, and intensity of drug action. Not
all drugs will show these substantial changes in their disposition as a function of
the type and volume of fluid ingested, but it is wise to instruct patients to be consistent
in their chosen method of ingesting medications.
As previously mentioned, the pH of the stomach may play a role in the rate of
absorption of drugs. In general, weakly basic drugs, such as antihistamines and nasal

decongestants, dissolve rapidly into the low pH environment of the stomach due to
the favorable ionization profile. Conversely, weakly acidic drugs, such as most
nonsteroidal antiinflammatory drugs (NSAIDs), are poorly soluble in the stomach
because acid molecules tend to remain unionized in strongly acidic environments.
One of the fundamental steps in the absorption process is the dissolution (or solvation)
of the drug molecules into stomach fluids from the administered dosage form.
If a drug is poorly soluble in the stomach and, as a result, the dissolution of the
drug molecules is slow, then the rate of absorption of the drug will decrease.
Paradoxically, a solubilized drug in an ionized state is considered to be poorly
absorbed. Drugs must be deionized to cross a lipophilic biological membrane, unless
a specific active transport mechanism exists to facilitate its movement across membranes.
Ideally, a drug molecule must be ionized to facilitate its dissolution and then
unionized to be absorbed. In reality, even ionized drug molecules are absorbed well
in the small intestine due to its tremendous surface area and lengthy residence time.
Table 2.3 displays the pH values and residence times of various portions of the GIT
during a fasted condition.

Intestinal Transit
Whereas the GER is sensitive to ingested solids and liquids, the intestinal emptying
rate is virtually independent of food or liquid ingestion.9 Numerous drugs,
however, can affect intestinal tone and motility. Stimulant laxatives increase the
movement of material from the small intestine distally, and this disruption in homeostasis
can easily affect the extent of drug absorption. Alternatively, antidiarrheals,
such as loperamide as well as narcotic analgesics, significantly slow intestinal
motility, and this may alter the extent of drug absorption. Concomitantly administered
medications that affect intestinal tone also affect intestinal transit to a greater
degree than food ingestion.
Drug Dissolution
The physical and chemical microphenomena that characterize drug dissolution
are covered in great detail in several biopharmaceutics textbooks. It is important to
mention in this forum a few basic concepts of drug dissolution. The measurement
of the rate of drug dissolution is a prime aspect in the Food and Drug Administration
(FDA) review of new drug applications. As previously mentioned, weakly basic
drugs dissolve well in acidic environments and weakly acidic drugs dissolve well
in basic environments. If food (solid or liquid) alters the pH of the stomach fluid,
then the dissolution rate of weak acids and bases will be affected.
The dissolution rate of many drugs is slower than the overall rate of drug
absorption. For such drugs, the dissolution rate limits their absorption. Tablets,
capsules, and other compressed, oral dosage forms typically belong to this category.
Circumstances that influence the dissolution rate for these drugs will have a substantial
impact on drug absorption. Whereas food and calorie-laden liquids reduce
the gastric emptying rate and thereby reduce the rate of absorption of drugs, the
effect of food on the dissolution rate of drug molecules is not as clear. The dissolution
rate of numerous drugs is unaffected by the ingestion of food; however, this is not
the case for all drugs.
In general, the dissolution rate of highly lipophilic drugs is enhanced when the
drug is taken with food, especially foods rich in fat. A great example is the original
formulation of the antifungal drug, griseofulvin. The dissolution rate and, thus, the
rate of absorption of griseofulvin is substantially increased when taken with food.
The dissolution rate of highly lipophilic drugs, therefore, may be enhanced when
taken with a fatty meal. In the case of griseofulvin, its absorption has been remarkably
enhanced by reducing the particle size of the drug aggregates and thus improving
its dissolution characteristics.
Complexation and Degradation
In addition to the influence on the GER and dissolution rate, the ingestion of
food may endanger the drug molecule. These dangers are manifested in the forms
of acidic degradation, food–drug adsorption, and complexation. Any of these may
significantly reduce or prevent drug absorption.
Acidic degradation of acid-sensitive drugs is a primary concern when drugs and
food are taken together. Classic examples of acid-sensitive drugs include aspirin and
the various first-generation penicillins. If the residence time of these drugs in the
stomach is increased by the presence of food, then the degradation of these drugs
increases. As a result, the extent of drug absorption may be substantially reduced
because the active degradation reduces the amount of drug available to be transported
across the mucosa and distributed in the circulation.
Drug molecules may adsorb onto food components and, thus, may lead to a
reduction in the rate and extent of absorption. Conversely, food particles may interact
with drug molecules in the stomach and small intestine. Numerous instances of
multivalent cation complexation with the older tetracyclines exist. When these medications
are taken with food (or other drug preparations) containing iron, calcium,
aluminum, magnesium, and other multivalent cations, insoluble complexes may be
formed that render the drug unabsorbable.
The effect of food on the rate and extent of absorption, by any of the above
mechanisms, is generally considered to be less critical when drugs are taken 30 min
or more before feeding or 2 h postprandial. Although the preceding sections contained
several examples of prescription drugs, these types of interactions may easily
occur with OTC medications. Indeed, with the recent increasing trend of prescription
to OTC movement, these interactions may become more prevalent.