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.

PHARMACOKINETIC PARAMETERS of Biopharmaceutics of Orally Ingested Products

This discussion limits its consideration to the movement of orally ingested drugs
through the gastrointestinal tract (GIT). The movement is active rather than passive.
During the sequence from ingestion to elimination, a variety of active processes
common to both foods and drugs play important roles. Several pharmacokinetic
parameters are used to judge the clinical importance of food/drug interactions.
Pharmacy: Basic Concepts demonstrated that the appearance and disappearance of drug concentrations
in whole blood or blood components (principally plasma or serum) are the
primary measures of drug movement into target tissues. Pharmacologic effects occur
when the drug reaches these sites in appropriate amounts. The plasma or serum drug
concentration vs. time profile of a typical, immediate-release tablet is given in Figure
2.1. From this profile, several meaningful parameters can be obtained that relate the
rate and extent of drug absorption from the dosage form. The rate refers to how fast
the drug reaches the systemic circulation, which is generally considered to translate
into the onset and intensity of the intended drug effect. The extent refers to the total
exposure of the drug in the bloodstream. The extent of drug absorption is integral
in determining the duration, termination, intensity, and therapeutic index of the drug.
Drugs may be absorbed by various routes and processes. For most drugs, the
rate of absorption can be classified as a zero-order or first-order rate process.
Although an in-depth discussion of rate orders of reactions is beyond the mission
of this chapter, a general understanding of these rate orders facilitates a deeper
understanding of how food may alter overall rates of drug absorption. The zeroorder
rate process proceeds in a constant fashion and without regard to any other
factor. In terms of drug absorption, a certain amount of the drug will be absorbed
in a given time period and will not change. Usually, zero-order absorption is the

result of specific drug carriers working at their maximal capacity. The first-order
rate process differs considerably from that of a zero-order process. The first-order
rate process will increase as the concentration of drug at the absorption site increases.
In terms of drug absorption, the rate of drug absorption increases as the drug
concentration at the absorption site increases. Figure 2.2 displays the zero- and firstorder
rate processes as a function of drug concentration at the absorption site.
Rate of Absorption (KA)
The overall rate of drug absorption, KA, represents the sum of many individual
rates of processes that eventually lead to the appearance of drug in the bloodstream.
These individual rates include: (1) the rate of disintegration of the dosage form, (2)
the rate of dissolution (or solvation) of the drug from the disintegrated dosage form,
(3) the rate of gastric emptying, (4) the rate of drug degradation in the GIT, and (5)
the rate of intestinal emptying (transit). If food interferes with any of these processes,
then the overall rate of absorption will be affected. Several different methods of
determining the rate of absorption exist, and these methods are covered in detail in
clinical pharmacokinetics textbooks. In this chapter, we will focus on the use of the
KA term, rather than its discovery from experimental data.
As explained previously, one cannot inspect a plasma-drug concentration vs.
time profile and identify the component of the curve that represents KA. KA is
determined, however, by mathematical treatment of the plasma-drug concentration
vs. time data. KA is used to calculate a tangible parameter called the time to maximal
drug concentration (TMAX). This parameter also corresponds to the time to peak
absorption. Figure 2.3 relates TMAX to other clinical pharmacokinetic parameters
important in the assessment of drug absorption. When considering the implications
of the magnitude of KA, one sees that a small TMAX value leads to a rapid onset of
action. Thus, a rapid onset of action correlates to a small TMAX value, which in turn
is proportional to a rapid KA. For certain drugs, food may enhance the rate of
absorption, while the same food may substantially reduce the rate of absorption of
other drugs.

Maximal Drug Concentration (CMAX)
The maximal concentration or peak concentration of drug in plasma after a single
dose occurs at TMAX. Stated differently, CMAX is a function of and is inversely related
to TMAX. CMAX directly impacts the intensity of the pharmacological and/or toxicological
drug action. Therefore, circumstances that may slow the rate of absorption
(and thus increase TMAX) may result in a decrease in CMAX. This in turn may reduce
the intensity of drug action. Figure 2.3 visually demonstrates the relationship
between TMAX and CMAX.
Area under the Plasma Concentration vs. Time Curve (AUC)
AUC is the fundamental pharmacokinetic parameter that denotes the extent of
drug absorption. Many dosing regimens are based on the total systemic exposure of
a drug after a given dose as measured by the plasma-drug AUC. The unusual
dimension of the AUC term (mass × time/volume) is due to the formula used to
derive AUC. Two (x, y) coordinates on the plasma-drug concentration vs. time curve
create a trapezoid, and, as such, the area contained in that trapezoid can be calculated
with elementary geometry. Thus, the “AUC” term is the sum of all the individual
trapezoids formed by the drug plasma concentration vs. time data. The magnitude
of the AUC value influences the intensity, duration and termination of activity (see
Figure 2.1). AUC is also governed by metabolic and elimination pathways; therefore,
the prediction of how food may directly alter the magnitude of AUC is confounding.
One of the main elimination routes of any drug absorbed in the GIT occurs
during its first pass through the liver. As a result of this pathway that is designed to
protect the body from toxins, it is quite likely that not all of the drug that is absorbed
will reach the systemic circulation. The AUC value is thus used to calculate the
bioavailability (F) of the drug or the percentage of the dose that reaches the systemic
circulation. The following expressions describe the relationships among the parameters
discussed in this section.
AUC ∝ F
TMAX ∝ 1/KA
CMAX ∝ KA
CMAX ∝ F