BIOPHARMACEUTICS

PHYSIOLOGICAL FACTORS INFLUENCING ORAL DRUG ABSORPTION

Lecture 2

Dr Omar A Hamid

Department of pharmaceutics

The gastrointestinal tract - physiology and drug absorption

STOMACH
• PH 1-3
• Variable transit time
• Secretion of Pepsin

SMALL INTESTINE
• pH 5-7
• Secretion of pancreatic enzyme and bile salts
• Transit time 3 hours
• Large surface area

LARGE INTESTINE OR COLON

• pH 6-7.5
• Bacterial enzymes
• Long and variable transit time
• Increased viscosity due to water absorption
The gastrointestinal tract is complex.
• the rate and extent of appearance of intact
drug in the systemic circulation depends on a
succession of kinetic processes.

• The slowest step in this series, which is

known as the rate-limiting step. Controls the
overall rate and extent of appearance of
intact drug in the systemic circulation.

• The particular rate-limiting step will vary

from drug to drug.

a schematic illustration of the steps involved in the

release and absorption of a drug from a tablet dosage
form

The potential rate-limiting steps include

• Dissolution-rate limited: Poor aqueous solubility drugs.

• Permeability-limited: for a drug that has a high aqueous solubility its dissolution will be
rapid and the rate at which the drug crosses the gastrointestinal membrane may be the
rate-limiting step.

• The rate of release of the drug from the dosage form (controlled-release dosage forms).

• The rate at which the stomach empties the drug into the small intestine.

• The first pass effect: the rate at which the drug is metabolized:
• Mucosal cells .
• During its initial passage through the liver.
 PHYSIOLOGICAL FACTORS INFLUENCING ORAL DRUG ABSORPTION

• The transit of pharmaceuticals in the gastrointestinal tract

• Barriers to drug absorption

• The environment within the lumen

• The unstirred water layer

• Gastrointestinal membrane

• Presystemic elimination

THE TRANSIT OF PHARMACEUTICALS IN THE GASTROINTESTINAL

TRACT

• Small intestine is the major site of drug absorption, and thus the time a drug is
present in this part of the gastrointestinal tract is extremely significant.

• If sustained- or controlled-release drug delivery systems are being designed, it is

important to consider their transit times through certain regions of the GIT.

• In general, most dosage forms, when taken in an upright position, transit through
the oesophagus quickly, usually in less than 15 seconds.

• Transit through the oesophagus is dependent both upon the dosage form and
posture.

• Tablets/capsules taken in the supine position, especially if taken without water, are
liable to lodge in the esophagus.
• Transit of liquids, for example, has always been observed to be rapid, and in general faster
than that of solids.

• A delay in reaching the stomach may well delay a drug's onset of action or cause damage or
irritation to the oesophageal wall, e.g. potassium chloride tablets.

Gastric emptying

The time a dosage form takes to traverse the stomach is usually termed the gastric residence
time, gastric emptying time.

Gastric emptying of Pharmaceuticals is highly variable and is dependent on the dosage form
and the fed/fasted state of the stomach.

Normal gastric residence times usually range between 5 minutes and 2 hours.

• In the fasted state is characterized by a repeating cycle of four phases.

• Phase I is a relatively inactive period of 40-60 minutes with only rare contractions
occurring.

• Increasing numbers of contractions occur in phase II, which has a similar duration to
phase I.

• Phase III is characterized by powerful peristaltic contractions which open the

pylorus at the base and clear the stomach of any residual material.

• Phase IV is a short transitional period between the powerful activity of phase III and
the inactivity of phase I.

• The cycle repeats itself every 2 hours until a meal is ingested and the fed state or
motility is initiated.
Fed state
• Two distinct patterns of activity have been observed:
• The proximal stomach relaxes to receive food.

• Peristalsis - contractions of the distal stomach – serve to mix and break down
food particles and move them towards the pyloric sphincter.

• The pyloric sphincter allows liquids and small food particles to empty while
other material is retropulsed into the antrum of the stomach and caught up by
the next peristaltic wave for further size reduction before emptying.

• Thus in the fed state liquids, pellets and disintegrated tablets will tend to empty
with food, yet large sustained or controlled release dosage forms can be retained in
the stomach for long periods of time.

• In the fasted state the stomach is less discriminatory between dosage form types,

Many factors influence gastric emptying, include:

• The type of dosage form

• The presence and composition of food:

In general, food, particularly fatty foods, delays gastric emptying and hence
the absorption of drugs. Therefore, a drug will reach the small intestine most
rapidly if it is administered with water to a patient whose stomach is empty.

• The postural position,

• The effect of drugs and disease state.

• Metoclopramide, which is a drug that increases gastric emptying rate, has

been shown to increase the rate of absorption of paracetamol, whereas
• proprantheline, a drug which delays gastric emptying, has been shown to
delay its rate of absorption.
Small intestinal transit

• The propulsive movements primarily determine the intestinal transit rate and hence the
residence time of the drug or dosage form in the small intestine.
• The small intestinal transit time (that is, the time of transit between the stomach and the
caecum) is an important factor with respect to drug bioavailability.
• Small intestinal transit is constant, at around 3 hours.
• In contrast to the stomach, the small intestine does not discriminate between solids and
liquids.

• Small intestinal residence time is particularly important for some dosage forms
• that release their drug slowly (e.g. controlled- sustained- prolonged-release systems) as
they pass along the length of the gastrointestinal tract;
• enteric-coated dosage forms which release drug only when they reach the small intestine;
• drugs that dissolve slowly in intestinal fluids;
• and drugs that are absorbed by intestinal carrier-mediated transport systems.

BARRIERS TO DRUG ABSORPTION

Some of the barriers to absorption that a drug may encounter once it is released from its
dosage form and has dissolved into the gastrointestinal fluids are shown in the figure below.
The environment within the lumen

Gastrointestinal pH
• The pH of fluids varies considerably along the length of the gastrointestinal tract.

• Gastric fluid is highly acidic, normally exhibiting a pH within the range 1-3.5 in healthy
people in the fasted state.
• Typical gastric pH values following a meal are in the range 3-7. Depending on meal size
the gastric pH returns to the lower fasted-state values within 2-3 hours.

• Thus only a dosage form ingested with or soon after a meal will encounter these higher
pH values. This may be an important consideration in terms of the chemical stability of a
drug, or in achieving drug dissolution or absorption.

• Intestinal pH values are higher than gastric pH values owing to the neutralization of the
gastric acid with bicarbonate ions secreted by the pancreas into the small intestine. There
is a gradual rise in pH along the length of the small intestine from the duo-denum to the
ileum.

• The pH drops again in the colon, as the bacterial enzymes, which are localized in the
colonic region, break down undigested carbohydrates into short-chain fatty acids;
this lowers the pH in the colon to around 6.5.
 The gastrointestinal pH may influence the absorption of drugs in a variety of ways:

• It may influence the chemical stability of the drug in the lumen, its dissolution or its
absorption, if the drug is a weak electrolyte.

• Chemical degradation due to pH-dependent hydrolysis can occur in the gastrointestinal

tract. The result of this instability is incomplete bioavailability. The extent of
degradation of penicillin G (benzylpenicillin), the first of the penicillins, after oral
administration depends on its residence time in the stomach and gastric pH. This gastric
instability tends to preclude its oral use.

• The antibiotic erythromycin and proton pump inhibitors (e.g. omeprazole) degrade
rapidly at acidic pH values and therefore have to be formulated as enteric-coated dosage
forms to ensure good bioavailability.

Luminal enzymes :
• Pepsins and the proteases are responsible for the degradation of protein and peptide
drugs in the lumen. Other drugs that resemble nutrients, such as nucleotides and
fatty acids, may also be susceptible to enzymatic degradation.

• The lipases may also affect the release of drugs from fat/oil-containing dosage forms.

• Bacteria, which are mainly localized within the colonic region of the gastrointestinal
tract, also secrete enzymes which are capable of a range of reactions. These enzymes
have been utilized when designing drugs or dosage forms to target the colon.

• Sulphasalazine, for example, is a prodrug of 5-aminosalicylic acid linked via an azo

bond to sulphapyridine. The sulphapyridine moiety makes the drug too large and
hydrophilic to be absorbed in the upper gastrointestinal tract, and thus permits its
transport intact to the colonic region, where the bacterial enzymes reduce the azo bond
and release the active drug, 5-aminosalycylic acid, for local action in colonic diseases
such as inflammatory bowel disease.
 Influence of food in the gastrointestinal tract

• Complexation of drugs with components in the diet: Tetracycline, forms non-

absorbable complexes with calcium and iron, and thus it is advised that patients do
not take products containing calcium or iron, such as milk, iron preparations or
indigestion remedies, at the same time of day as the tetracycline.

• Alteration of pH In general, food tends to increase stomach pH by acting as a

buffer. This is liable to decrease the rate of dissolution and subsequent absorption of
a weakly basic drug and increase that of a weakly acidic one.

• Alteration of gastric emptying: foods containing a high proportion of fat, and some
drugs, tend to reduce gastric emptying and thus delay the onset of action of certain
drugs.

• Stimulation of gastrointestinal secretions

• GI secretions (e.g. pepsin) produced in response to food may result in the degradation
of drugs that are susceptible to enzymatic metabolism.
• The ingestion of food, particularly fats, stimulates the secretion of bile. Bile salts are
surface active agents and can increase the dissolution of poorly soluble drugs,
thereby enhancing their absorption. However, bile salts have been shown to form
insoluble and hence non-absorbable complexes with some drugs, such as neomycin,
kanamycin and nystatin.

• Competition between food components and drugs for specialized absorption

mechanisms

• Increased viscosity of gastrointestinal contents Which may result in

• A reduction in the rate of drug dissolution.
• A decrease in the rate of diffusion of a drug in solution from the lumen to the
absorbing membrane lining the gastrointestinal tract.
• Food-induced changes in presystemic metabolism: Grapefruit juice, for example, is
capable of inhibiting the intestinal cytochrome P450 (CYP3A family) and thus, taken with
drugs that are susceptible to CYP3A metabolism, is likely to result in their increased
bioavailability. Clinically relevant interactions exist between grapefruit juice and the
antihistamine terfenadine, the immunosuppressant cyclosporin, the protease inhibitor
saquinavir and the calcium channel blocker verapamil.

• Food-induced changes in blood flow Blood flow to the gastrointestinal tract and liver
increases shortly after a meal, thereby increasing the rate at which drugs are presented to the
liver. The metabolism of some drugs (e.g. propranolol, hydralazine, dextropropoxyphene) is
sensitive to their rate of presentation to the liver: the faster the rate of presentation the larger
the fraction of drug that escapes first-pass metabolism. This is because the enzyme systems
responsible for their metabolism become saturated by the increased rate of presentation of
the drug to the site of biotransformation. For this reason, the effects of food serve to
increase the bioavailability of some drugs that are susceptible to first-pass metabolism.

Disease state and physiological disorders

• Local diseases can cause alterations in gastric pH that can affect the stability, dissolution
and/or absorption of the drug.

• For example, partial or total gastrectomy results in drugs reaching the duodenum more
rapidly than in normal individuals. This increased rate of presentation to the small
intestine may result in an increased overall rate of absorption of drugs that are primarily
absorbed in the small intestine.

• However, drugs that require a period of time in the stomach to facilitate their dissolution
may show reduced bioavailability in such patients.