‘


‘

Absorption is defined as the process of movement of unchanged drug from the site of
administration to systemic circulation (or)the process of movement of unchanged drug from the
site of administration to the site of measurement i.e., plasma. This condition is taken into account
only when there is loss of drug that occurs after oral administrationdue to first pass metabolism
or presystemic metabolism. The drugs which have to enter the systemic circulation have to be
administered through three major routes they are enteral route, parentral route, and topical routes.

Many drugs are not administered orally because of drug instability in the gastrointestinal
tract or drug degradation by the digestive enzymes in the intestine. For example, erythropoietin
and human growth hormone (somatrophin) are administered intramuscularly, and insulin is
administered subcutaneously or intramuscularly, because of the potential for degradation of these
drugs in the stomach or intestine. Biotechnology products () are often too labile to be
administered orally and therefore are usually given parenterally. Drug absorption after
subcutaneous injection is slower than intravenous injection. Pathophysiologic conditions such as
burns will increase the permeability of drugs across the skin compared with normal intact skin.

When a drug is administered by an extravascular route of administration (eg, oral, topical,

intranasal, inhalation, rectal), the drug must first be absorbed into the systemic circulation and
then diffuse or be transported to the site of action before eliciting biological and therapeutic
activity. The general principles and kinetics of absorption from these extravascular sites follow
the same principles as oral dosing, although the physiology of the site of administration differs.

½  ‘
‘ ‘ 
‘

Many drugs administered by extravascular routes are intended for local effect. Other drugs are
designed to be absorbed from the site of administration into the systemic circulation. For
systemic drug absorption, the drug must cross cellular membranes. After oral administration,
drug molecules must cross the intestinal epithelium by going either through or between the
epithelial cells to reach the systemic circulation. The permeability of a drug at the absorption site

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into the systemic circulation is intimately related to the molecular structure of the drug and to the
physical and biochemical properties of the cell membranes. Once in the plasma, the drug may
have to cross biological membranes to reach the site of action. Therefore, biological membranes
potentially pose a significant barrier to drug delivery.‘

‘‘‘‘‘‘‘‘‘‘

‘  


 is the process of drug movement across a cell. Some polar
molecules may not be able to traverse the cell membrane but, instead, go through gaps or  ‘

 between cells, a process known as 

‘
‘ 


. shows the difference
between the two processes. Some drugs are probably absorbed by a mixed mechanism involving
one or more processes.

When a drug is administered by an extravascular route of administration (eg, oral, topical,

intranasal, inhalation, rectal), the drug must first be absorbed into the systemic circulation and
then diffuse or be transported to the site of action before eliciting biological and therapeutic
activity. The general principles and kinetics of absorption from these extra vascular sites follow
the same principles as oral dosing, although the physiology of the site of administration

Membranes are major structures in cells, surrounding the entire cell (plasma membrane)
and acting as a boundary between the cell and the interstitial fluid. In addition, membranes
enclose most of the cell organelles (e.g., the mitochondrion membrane). Functionally, cell
membranes are semi permeable partitions that act as selective barriers to the passage of
molecules. Water, some selected small molecules, and lipid-soluble molecules pass through such
membranes, whereas highly charged molecules and large molecules, such as proteins and
protein-bound drugs.

u 
 
‘ 
‘

‘‘

The most common route of administration for the drugs which are systemically active is oral
route. so gastro intestine plays a major role in absorption of drugs.

To know the mechanism of drug absorption the cell membrane structure and physiology
are to be studied,all drugs for absorption, distribution, elimination from the body should pass

through different biological membranes and barriers. Absorption through gastrointestinal route is
most common for systemically acting drugs such movement of drug is called DRUG
TRANSPORT.

The cellular membrane consists of a double layer of amphiphilic phospholipids molecules

arranged in such a fashion that hydrocarbon chains are oriented inwards to form the their
hydrophobic or lipophilic phase and their polar heads oriented to form the outer and inner
hydrophilic boundaries of the cellular membrane that face the surrounding aqueous environment.
Globular protein molecules are associated on either side of these hydrophilic boundaries and also
interspersed within the membrane structure. it is compared as Ú
 ‘   where a
bimolecular layer of lipids is contained between two parallel monomolecular layers of proteins.
The hydrophobic core of the membrane is responsible for relative impermeability of polar
molecules. Aqueous filled pores are present in the membrane structure through which inorganic
ions and small organic water-soluble molecules like urea can pass. The biomembrane acts like a
semi permeable barrier permitting rapid and limited passage of some compounds.

The transmembrane movement of drugs is influenced by the composition and structure of

the plasma membranes. Cell membranes are generally thin, approximately 70 to 100 Å in
thickness. Cell membranes are composed primarily of phospholipids in the form of a bilayer
interdispersed with carbohydrates and protein groups. There are several theories as to the
structure of the cell membrane. The   ‘ 
or  ‘ÚÚ
‘

‘originally proposed
by , considers the plasma membrane to be composed of two layers of phospholipid between two
surface layers of proteins, with the hydrophilic "head" groups of the phospholipids facing the
protein layers and the hydrophobic "tail" groups of the phospholipids aligned in the interior. The
lipid bilayer theory explains the observation that lipid-soluble drugs tend to penetrate cell
membranes more easily than polar molecules. However, the bilayer cell membrane structure does
not account for the diffusion of water, small-molecular-weight molecules such as urea, and
certain charged ions.

The  ‘ Ú
 ‘ Ú
, proposed by, explains the transcellular diffusion of polar
molecules. According to this model, the cell membrane consists of globular proteins embedded
in a dynamic fluid, lipid bilayer matrix. These proteins provide a pathway for the selective

Œ
transfer of certain polar molecules and charged ions through the lipid barrier. As shown in,
transmembrane proteins are interdispersed throughout the membrane. Two types of pores of
about 10 nm and 50 to 70 nm were inferred to be present in membranes based on capillary
membrane transport studies. These small pores provide a channel through which water, ions, and
dissolved solutes such as urea may move across the membrane.

Mechanism of drug absorption

In the mechanism of drug absorption slowly absorbed drug may fail to show therapeutic response
as the plasma concentration for the desired effect is never achieved whereas rapidly absorbed
drug attains a therapeutic level easily to elicit pharmacological action.

It involves different mechanism for drug absorption.

1.Transcellular/intracellular transport

a) Passive transport

i.‘ Passive diffusion

ii.‘ Pore transport
iii.‘ Ion-pair transport
iv.‘ Facilitated/mediated diffusion

b) Active transport

i.‘ Paracellular/intercellular transport

ii.‘ Vesicular transport
‘ Pinocytosis
‘ Phagocytosis

[
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‘ ‘ 
‘
‘
  ‘
‘    ‘ 
ë

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  ‘
ë it is defined as the passage of drug across GI epithelium.

Three steps are involved in transcellular membrane

permeation of GI epithelial cell membrane, a lipoidal barrier-this is the major obstacle for drug
absorption, movement across the intracellular space which is called as cytosol, permeation of
lateral and basolateral membrane.

1)Passive transport processesë this transport does not require energy other than that of
molecular motion which is called as Brownian motion.

Passive diffusionë it is also called as non ionic diffusion, majority of drugs pass through this
type. Driving force for this process is  ‘  ‘ 
 ‘It is defined as difference drug
concentration on either side of the membrane. The drug movement is a result of kinetic energy of
molecules. Since it does not need any energy it is called as passive diffusion, the drug present in

r
the aqueous solution at the absorption site partitions and dissolves in the lipid material of the
membrane and finally leaves it by dissolving again in an aqueous medium, this time at the inside
of the membrane.

Passive diffusion is best expressed by

‘
‘ ‘
‘


It states the drug molecules

diffuse from a region of higher concentration to one of lower concentration until equilibrium is
attained and that the rate of diffusion is directly proportional to the concentration gradient across
the membrane. It can be mathematically expressed by the following equationë

dQ/dt = DAKm/w/h(Cgit-C)

Where,

dQ/dt = rate of drug diffusion.it also represents the rate of appearance of drug in blood

D = diffusion coefficient of the drug through the membrane

A = surface area of the absorbing membrane for drug diffusion

Km/w = partition coefficient of the drug between the lipoidal membrane and the aqueous GI fluids

(CGIT ±C) = difference in the concentration of drug in the GI fluids and the plasma, called as the
concentration gradient

h = thickness of the membrane

When the drug is ingested, CGIT>>C and a large concentration gradient exists thereby acting as
the driving force for absorption. As equilibrium approaches, the drug diffusion should stop and
consequently a large fraction of drug may remain unabsorbed. Once the passive absorbed drug
enters blood, it is rapidly swept away and distributed into a much larger volume of body fluids
and hence, the concentration of drug in plasma. This condition is called as 
‘ 

‘ for
drug absorption.

Permeability refers to the ease with which a drug can penetrate or diffuse through a membrane.
Due to sink condition, the concentration of drug in plasma C is very small in comparison to CGIT.

dQ/dt = PCGIT

]
Pore transportë it is also called as convective transport. This mechanism is responsible for
transport of molecules into the cells through protein channels present in the cell membrane.

The driving force s constituted by the hydrostatic pressure or osmotic difference across the
membrane due to which small solid molecules occurs through such aqueous channels. Water flux
that promotes such a transport is called as solvent drag. This process is important in the
absorption of low molecular weight, low molecular size and generally water soluble drugs
through narrow, aqueous ±filled channels or pores in the membrane structure-urea,waterand
sugars. Chain-like or linear compounds of molecular weight upto 400 daltons can be absorbed.

Ion-pair transportë this mechanism explains the absorption of drugs like quaternary
ammonium compounds and sulphonic acids, which ionize under all pH conditions, is ion-pair
transport. Although they have low o/w partition coefficient values, such neutral complexes have
both the required lipophilicity as well as aqueous solubility for passive diffusion. This
phenomenon is called as ion-pair transport.

Carrier-mediated transport the mechanism is thought to involve a component of the

membrane called as    that binds reversibly with the solute molecules to be transported.
This is specialized transport mechanisms without which many essential water-soluble nutrients
like monosaccharides, amino acids and vitamins will poorly absorbed. The carrier-solute
complex traverses across the membrane to the other side where it dissociates and discharges the
solute molecule. The carrier then returns to its original site to complete the cycle by accepting a
fresh molecule of solute. The carrier in the membrane may be a protein or an enzyme or some
other component of the membrane.

è
x  ‘
‘  ‘   ‘




 ‘  ‘ 
‘   ë this transport mechanism requires energy in the form of
ATP. It is subdivided into primary and secondary active transport.

Primary active transportë this process requires direct ATP. The process transfers only one ion
or molecule in only one direction, and hence called as uniporter e.g. absorption of glucose

a.‘ Ion transportersë these are responsible for transport of ionsë n or out of the cell.
Suitable example for this process is ATP-driven ion pump is proton pump which is
implicated in acidification of intracellular compartments. Two types of ion transporters
which play important role in intestinal absorption of drugs- organic anion transporter,
organic cation transporter.
b.‘ ABC (ATP-binding cassette) transportersë these are responsible for transporting
small foreign molecules especially out of cells i.e. exorption a classical example for ATP
transporter is p-glycoprotein. The latter is responsible for pumping hydrophobic drugs
especially anti cancer drugs out of cells.Presence of large quantity of this protein thus
makes the cells resistant to a variety of drugs used in cancer chemotherapy, the
phenomena is called as multi-drug resistance (MDR) protein.

w
Secondary active transportë in this process there is no direct requirement of ATP i.e. it uses
the existing concentration gradient. The energy required to transport an ion or molecule aids
transport of another ion or molecule either in same direction or in opposite direction. it is sub-
divided into

a.‘ Symport (co-transport)ë involves movement of two molecules in same direction. e.g. +-
glucose symporter uses the same the potential energy of the Na+concentration gradient to
move glucose against its concentration gradient another example for symporter is peptide
transporter.
b.‘ Antiport (counter-transport)ë it involves movement of molecules in the opposite direction
e.g.explusion of H+ ions using the Na+ gradient in the kidneys.

Advantages of active transportë

1. Active transport of drug is transported from lower to one of higher concentration i.e. against
concentration gradient or uphill transport.

2. The process is faster than passive diffusion.

3. Since the process is uphill transport, the energy is required in the work done by the carrier.

As the process requires expenditure of energy, it can be inhibited by metabolic poisons that
interfere with energy production like fluorides, cyanides and lack of oxygen. Endogenous
substances that are transported actively include sodium, potassium, calcium, iron, glucose and
some amino acids, vitamins. Drugs having structural similarities to such agents are absorbed
actively particularly agents acting in chemotherapy.

     ‘ 
ë it is defined as the transport of drugs through the junctions

between the GI epithelial cells. The two paracellular transport mechanisms involved in drug
absorption are

A. Permeation through tight junctions of epithelial cellsë in this process the openings
are little bigger than the aqueous pores. Compounds like insulin,cardiac glycosides are taken up
by this mechanism

Õ
B. Persorptionë permeation of drugs through temporary openings formed by shedding of two
neighboring epithelial cells into the lumen.

3.Vesicular transportë this method is also energy dependent process but involves transport of
substances within vesicles into cells.

Endocytosisë‘ It is minor transportmechanism which involves engulfing extracellular material

within a segment of the cell membrane to form a saccule or a vesicle which is then pinched-off
intracellular. In this method the drug may not be aqueous solution in order to be absorbed.

This mechanism is responsible for the cellular uptake of macromolecular nutrients like fats and
starch. Other advantage of this method is that the drug is absorbed in the lymphatic circulation
thereby by-passing first-pass hepatic metabolism

a.‘ Pinocytosis (cell drinking)ë absorptive uptake of solid particulates.

b.‘ Phagocytosis (cell eating)ë uptake of fluid solute.

Orally administered Sabin polio vaccine, large protein molecules and botulism toxins are thought
to be absorbed by pinocytosis. Some times an endocytic vesicle is transferred from one
extracellular compartment to another. such phenomena is called as transcytosis.


‘
‘‘

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‘

The normal physiologic processes of the alimentary canal may be affected by diet, contents of
the gastrointestinal (GI) tract, hormones, the visceral nervous system, disease, and drugs. Thus,
drugs given by the enteral route for systemic absorption may be affected by the anatomy,
physiologic functions, and contents of the elimentary tract. Moreover, the physical, chemical,
and pharmacologic properties of the drug itself will also affect its own absorption from the
alimentary canal.

The 
ڑ consists of the alimentary canal from the mouth to the anus. The
major physiologic processes that occur in the GI system are secretion, digestion, and absorption.
Secretion includes the transport of fluid, electrolytes, peptides, and proteins into the lumen of the
alimentary canal. Enzymes in saliva and pancreatic secretions are also involved in the digestion

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of carbohydrates and proteins. Other secretions, such as mucus, protect the linings of the lumen
of the GI tract. Digestion is the breakdown of food constituents into smaller structures in
preparation for absorption. Food constituents are mostly absorbed in the proximal area
(duodenum) of the small intestine. The process of absorption is the entry of constituents from the
lumen of the gut into the body. Absorption may be considered as the net result of both lumen-to-
blood and blood-to-lumen transport movements.

Gastro intestinal tract is major region for absorption of drugs. The major components of the
stomach, small intestine, and large intestine. Small intestine is divided into duodenum, jejunum,
and ileum. The stomach is a pouch like structure lined with a relatively smooth epithelial surface.
Extensive absorption of weakly acidic and some weakly basic drugs can be demonstrated in the
stomach under experimental conditions. Ethanol is rapidly and absorbed from the ligated
stomach pouch of the dog.

Small intestine is the important site for drug absorption in gastrointestinal tract. it is also
important in carrier-mediated transport. The folds of intestinal mucosa are called as fold of
kercking. Proximal part of small intestine is the major area of absorption of dietary constituents
including monosaccharides, amino acids, vitamins and minerals. Large intestine, like stomach
has less irregular mucosa than that of the small intestine. This segment serves as a reserve area
for the absorption of drugs that have escaped absorption proximally.

Entire length of GI mucosa from stomach to large intestine is lined by thin layer of
mucopolysaccharides which is called as mucin. Which normally acts as impermeable barrier to
the particulate such as bacteria and food particles? The blood perfusing the gastrointestinal tract
plays a major role in drug absorption by continuously maintaining the concentration gradient
across the epithelial membrane. Polar molecules that are slowly absorbed show no dependence
on blood flow rate. The absorption rates of most of the drugs are intermediate dependent on
blood flow.

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½‘

Biopharmaceutical considerations in dosage form design to achieve the desired therapeutic effect
the drug product must have to deliver the active drug at an optimal rate and amount. The rate and
extent of drug absorption is called as bioavailability or systemic delivery to the body can be
varied from rapid and complete absorption to slow and sustained absorption depending upon the
therapeutic objective.

The chains of events that occurs in solid dosage form like tablet and capsules are
disintegration, granules of aggregates, conversion into fine particles. These steps can individually
convert into drug in solution form at absorption site. After this step the drug gets separated into
ionic and non-ionic drug forms which are present in GI lumen and they cross the barrier and
reach the distribution phase.

In a series of kinetic or rate processes the rate at which the drug reaches the systemic
circulation is determined as the slowest of the various steps involved in the sequence. Such steps
are called as   ‘   

‘ ‘   ‘ 
‘  ‘ "RDS . The rate and extent of the drug
absorption can be influenced by different factors which are

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 ‘    ‘


Physicochemical properties of drug

1.‘ Drug solubility and dissolution rate

2.‘ Particle size and effective surface area
3.‘ Polymorphism and amorphism
4.‘ Pseudopolymorphism
5.‘ Salt form of drug
6.‘ Lipophilicity of the drug
7.‘ pKa of the drug
8.‘ Drug stability
9.‘ Stereochemical nature of the drug

Pharmaco-technical factors

1.‘ Disintegration time

2.‘ Dissolution time
3.‘ Manufacturing variables
4.‘ Pharmaceutical ingredients
5.‘ Nature and type of dosage form
6.‘ Product age and storage conditions

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‘   ‘
.

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‘
½
‘
x‘
‘
½u‘x u‘
!
½ë

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The effect of drugs may vary among people of different age groups. In infants the drug
metabolism is poor, hepatic clearance is slow which prolongs the half life of the drugs. Infants
have smaller intestinal surface and comparatively less blood flow with adults. But they have
good gastric pH.

In elderly patients decreased intestinal surface area and GI blood flow, higher incidents of
achlorohydria and bacterial growth in small intestine and retards the drug absorption in both
cases.

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 ‘ 
 ½uë

Anatomically, a swallowed drug rapidly reaches the stomach. Eventually, the stomach empties
its contents into the small intestine. Because the duodenum has the greatest capacity for the
absorption of drugs from the GI tract, a delay in the gastric emptying time for the drug to reach
the duodenum will slow the rate and possibly the extent of drug absorption, thereby prolonging
the onset time for the drug. Some drugs, such as penicillin, are unstable in acid and decompose if
stomach emptying is delayed. Other drugs, such as aspirin, may irritate the gastric mucosa during
prolonged contact.

A number of factors affect gastric emptying time. Some factors that tend to delay gastric
emptying include consumption of meals high in fat, cold beverages, and anticholinergic drugs
Liquids and small particles less than 1 mm are generally not retained in the stomach. These small
particles are believed to be emptied due to a slightly higher basal pressure in the stomach over
the duodenum. Different constituents of a meal empty from the stomach at different rates.
Feldman and associates (1984) observed that 10 oz of liquid soft drink, scrambled egg (digestible
solid), and a radio-opaque marker (undigestible solid) were 50% emptied from the stomach in 30
minutes, 154 minutes, and 3 to 4 hours, respectively. Thus, liquids are generally emptied faster
than digested solids from the stomach.

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The movement of drug from stomach to small intestine is called gastric emptying. It is rate-
limiting step in drug absorption so bioavailability increases.

Gastric emptying is desired when

‘ Drug has rapid onset of action  sedatives.

‘ Drugs which are released in intestine  enteric coated tablets.
‘ Unstable drugs in gastric environment  pencillin G.

When higher absorption takes place in small intestine  vitamin B12.

Gastric emptying is delayed by administrating food. Delay of gastric emptying takes place

‘ When food promotes drug dissolution and absorption  Griseofulvin.

‘ Gastric fluids promote disintegration and dissolution of different dosage forms.
‘ When the drug dissolves slowly  griseofulvin.
‘ If the drug causes any gastric irritation  Aspirin, nitrofurantoin.

Gastric emptying is a first order process. Several parameters are used to quantify gastric
emptyingë

u ‘ 
‘  ‘is the speed at which the stomach content empty into the intestine.

Different factors affecting gastric emptying are

1.Volume of mealë larger the bulk of meal, longer the gastric emptying time.

2.Composition of mealë gastric emptying ranges for various food materials is carbohydrates
> proteins > fats. Bile which is excessively secreted by fat containing food materials has an
inhibitory effect on gastric emptying.

3.Physical state and viscosity of the mealë gastric emptying of liquids takes place in less
than one hour, whereas solid particles takes 6-7 hours of time period emptying, finally viscous
materials empty at slow rate when compared to less viscous materials.

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4.Temperature of the mealë higher or lower temperature of the ingested fluids when
compared to body temperature retards the gastric emptying.

5.Gastrointestinal pHë it gets slower at low pH and promoted at higher and alkaline pH. The
pH of the drugs depends on molecular weight.

6.Electrolytes and osmotic pressureë low salt concentration, isotonic solution, water rapidly
empties the stomach. higher electrolyte solutions decreases the gastric emptying

7.Body postureë gastric emptying is favoured in standing and lying to right side since this
posture provides the stomach down-hill path

8.Emotional stateë psychological disorder like stress and anxiety promotes gastric motility,
while depression retards.

9.Exerciseë evigorous physical training retards gastric emptying.

10.Disease stateë all gastro intestinal disorders and other diseases like gastroenteritis, gastric
ulcer, pyloric stenosis, diabetes and hypothyroidism causes retardation of gastric emptying.
Gastrectomy, hyperthyroidism, duodenal ulcers promotes gastric emptying.

11.Drugsë drugs that retard gastric emptying includes poorly soluble antacids-aluminium
hydroxide, anti cholinergics-atropine, propantheline, narcotic analgesics-morphine, tricyclic anti
depressants-imipramine, amitriptyline. Prokinetic drugs-Metoclopramide, domperidone and
cisapride stimulate gastric emptying.

Large particles, including tablets and capsules, are delayed from emptying for 3 to 6 hours
by the presence of food in the stomach. Indigestible solids empty very slowly, probably during
the interdigestive phase, a phase in which food is not present and the stomach is less motile but
periodically empties its content due to housekeeper wave contraction.

‘‘

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‘
‘

Passage of food material from the stomach to the intestine is called intestinal transit. since the
small intestine is the major site of absorption of most of the drugs, long intestinal transit time is
desirable for complete drug absorption. The residence time depends upon the intestinal motility
and contractions. The mixing movement of intestine that occurs due to peristaltic contractions
promotes the drug absorption.

Delayed intestinal transit is desirable forë

Drugs that dissolve or release slowly from their dosage form or when the ratio dose to solubility
is high, drugs that dissolve only in intestine, drugs which are absorbed from specific sites in the
intestine, when the drug penentrates the intestinal mucosa very slowly, when the absorption from
the colon is minimal.

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‘#

Tremendous 107 fold difference in the hydrogen ion concentration is observed between gastric
and colon fluids. The GI pH generally increases gradually from the stomach to the colon.

Disintegration of some dosage forms is pH sensitive. With enteric-coated formulations, the coat
dissolves only in the intestine and disintegration of tablet.

A large number of drugs are either weak acids or weak bases whose solubility is greatly
affected by pH. A pH that favours the formation of salt of the drug enhances the dissolution of
that drug. since the dissolution is rate-determining step in the drug absorption.

Depending upon the drug pKa and the drug is acidic or basic drug, the GI pH influences the
drug absorption by determining the amount of the drug that would exist in the unionized form at
the site of absorption.

GI pH also influences the chemical stability of the drugs the acidic stomach pH is known
to affect degradation of penicillin G and erythromycin this can be overcome by preparing
prodrug of such drugs that do not degrade or dissolve in acidic pH. e.g. erythromycin estolate.

‘
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 ‘
 
‘ ‘

Normal peristaltic movements mix the contents of the duodenum, bringing the drug particles into
intimate contact with the intestinal mucosal cells. The drug must have a sufficient time
(
 ‘ Ú) at the absorption site for optimum absorption. In the case of high motility in the
intestinal tract, as in diarrhea, the drug has a very brief residence time and less opportunity for
adequate absorption.

The average normal small intestine transit time (SITT) was about 7 hours in early studies
using indirect methods based on the detection of hydrogen after an oral dose of lactulose
(fermentation of lactulose by colon bacteria yields hydrogen in the breath). Newer studies using
gamma scintigraphy have shown SITT to be about 3 to 4 hours. Thus a drug may take about 4 to
8 hours to pass through the stomach and small intestine during the fasting state. During the fed
state, SITT may take 8 to 12 hours. For modified-release or controlled-dosage forms, which
slowly release the drug over an extended period of time, the dosage form must stay within a
certain segment of the intestinal tract so that the drug contents are released and absorbed before
loss of the dosage form in the feces. Intestinal transit is discussed further in relation to the design
of sustained-release products in .

In one study reported by , utilizing a radioopaque marker, mean mouth-to-anus transit

time was 53.3 hours. The mean colon transit time was 35 hours, with 11.3 hours for the right
(ascending transverse portion), 11.4 hours for the left (descending and portion of the transverse),
and 12.4 hours for the rectosigmoid colon. Dietary fiber has the greatest effect on colonic transit.
Dietary fiber increases fecal weight, partly by retaining water and partly by increasing bacterial
mass.

 

‘
‘ ‘u 
 
‘
 ‘

The blood flow to the GI tract is important in carrying absorbed drug to the systemic circulation.
A large network of capillaries and lymphatic vessels perfuse the duodenal region and
peritoneum. The splanchnic circulation receives about 28% of the cardiac output and is increased
after meals. Once the drug is absorbed from the small intestine, it enters via the mesenteric

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vessels to the hepatic-portal vein and the liver prior to reaching the systemic circulation. Any
decrease in mesenteric blood flow, as in the case of congestive heart failure, will decrease the
rate of drug removal from the intestinal tract, thereby reducing the rate of drug bioavailability.

The role of the lymphatic circulation in drug absorption is well established. Drugs are
absorbed through the lacteal or lymphatic vessels under the microvilli. Absorption of drugs
through the lymphatic system bypasses the first-pass effect due to liver metabolism, because
drug absorption through the hepatic-portal vein is avoided. The lymphatics are important in the
absorption of dietary lipids and may be partially responsible for the absorption for some
lipophilic drugs. Many poorly water-soluble drugs are soluble in oil and lipids, which may
dissolve in chylomicrons and be absorbed systemically via the lymphatic system. Bleomycin or
aclarubicin were prepared in chylomicrons to improve oral absorption through the lymphatic
system.

Effect of Food on Gastrointestinal Drug Absorptionë

The presence of food in the GI tract can affect the bioavailability of the drug from an oral drug
product. Digested foods contain amino acids, fatty acids, and many nutrients that may affect
intestinal pH and solubility of drugs. The effects of food are not always predictable and can have
clinically significant consequences. Some effects of food on the bioavailability of a drug from a
drug product includeë

‘ Delay in gastric emptying

‘ Stimulation of bile flow
‘ A change in the pH of the GI tract
‘ An increase in splanchnic blood flow
‘ A change luminal metabolism of the drug substance
‘ Physical or chemical interaction of the meal with the drug product or drug substance

Food effects on bioavailability are generally greatest when the drug product is administered
shortly after a meal is ingested. The nutrient and caloric contents of the meal, the meal volume,
and the meal temperature can cause physiologic changes in the GI tract in a way that affects drug

cÕ
product transit time, luminal dissolution, drug permeability, and systemic availability. In general,
meals that are high in total calories and fat content are more likely to affect GI physiology and
thereby result in a larger effect on the bioavailability of a drug substance or drug product. The
FDA recommends the use of high-calorie and high-fat meals to study the effect of food on the
bioavailability and bioequivalence of drug products.

The absorption of some antibiotics, such as penicillin and tetracycline, is decreased with
food; whereas other drugs, particularly lipid-soluble drugs such as griseofulvin and metazalone,
are better absorbed when given with food containing a high fat content. The presence of food in
the GI lumen stimulates the flow of bile. Bile contains bile acids, which are surfactants involved
in the digestion and solubilization of fats, and also increases the solubility of fat-soluble drugs
through micelle formation. For some basic drugs (eg, cinnarizine) with limited aqueous
solubility, the presence of food in the stomach stimulates hydrochloric acid secretion, which
lowers the pH, causing more rapid dissolution of the drug and better absorption. Absorption of
this basic drug is reduced when gastric acid secretion is reduced.

Some drugs, such as erythromycin, iron salts, aspirin, and no steroidal anti-inflammatory agents
(NSAIDs), are irritating to the GI mucosa and are given with food to reduce this irritation. For
these drugs, the rate of absorption may be reduced in the presence of food, but the extent of
absorption may be the same and the efficacy of the drug is retained.

Food may enhance the absorption of a drug beyond 2 hours after meals. For example, the
timing of a fatty meal on the absorption of cefpodoxime proxetil was studied in20 healthy adults.
The area under the plasma concentration±time curve and peak drug concentration were
significantly higher after administration of cefpodoxime proxetil tablets with a meal and 2 hours
after a meal relative to dosing under fasted conditions or 1 hour before a meal. The time to peak
concentration was not affected by food, which suggests that food increased the extent but not the
rate of drug absorption. These results indicate that absorption of cefpodoxime proxetil is
enhanced with food or if the drug is taken closely after a heavy meal.

Timing of drug administration in relation to meals is often important. Pharmacists

regularly advise patients to take a medication either 1 hour before or 2 hours after meals to avoid



any delay in drug absorption. Since fatty foods may delay stomach emptying time beyond 2
hours, patients who have just eaten a heavy, fatty meal should take these drugs 3 hours or more
after the meal, whenever possible. Products that are used to curb stomach acid secretion are
usually taken before meals, in anticipation of acid secretion stimulated by food. Famotidine
(Pepcid), and cimetidine (Tagamet) are taken before meals to curb excessive acid production.

Ticlopidine (Ticlid) is an antiplatelet agent that is commonly used to prevent

thromboembolic disorders. Ticlopidine has enhanced absorption after a meal. The absorption of
ticlopidine was compared in subjects who received either an antacid or food or were in a control
group (fasting). Subjects who received ticlopidine 30 minutes after a fatty meal had an average
of 20% increase in plasma concentration over fasting subjects, whereas antacid reduced
ticlopidine plasma concentration by approximately the same amount. There was a higher
gastrointestinal complaint in the fasting group. Many other drugs have reduced gastrointestinal
side effects when taken with food. The decreased gastrointestinal side effects associated with
food consumption may greatly improve tolerance and compliance in patients.

The double-peak phenomenon observed for cimetidine may be due to variability in

stomach emptying and intestinal flow rates during the entire absorption process after a single
dose. For many drugs, very little absorption occurs in the stomach. For a drug with high water
solubility, dissolution of the drug occurs in the stomach, and partial emptying of the drug into the
duodenum will result in the first absorption peak. A delay in stomach emptying results in a
second absorption peak as the remainder of the dose is emptied into the duodenum.

Gastric transporterë

Several transport proteins are expressed in the intestinal epithelial cells. Although some
transporters facilitate absorption, other transporters, such as P-glycoprotein may effectively
inhibit drug absorption. P-gp, an energy-dependent, membrane-bound protein, is an ‘




‘ that mediates the secretion of compounds from inside the cell back out into the
intestinal lumen, thereby limiting overall absorption. Thus, drug absorption may be reduced or
increased by the presence or absence of efflux proteins. The role of efflux proteins is generally
believed to be a defense mechanism for the body to excrete and reduce drug accumulation.

c
 P-glycoprotein is expressed also in other tissues such as the blood±brain barrier, liver,
and kidney, where it limits drug penetration into the brain, mediates biliary drug secretion, and
renal tubular drug secretion, respectively. Efflux pumps are present throughout the body and are
involved in transport of a diverse group of hydrophobic drugs, natural products, and peptides.
Many drugs and chemotherapeutic agents, such as cyclosporin A, verapamil, terfenadine,
fexofenadine, and most HIV-1 protease inhibitors are substrates of P-gp (see ). In addition,
individual genetic differences in intestinal absorption may be the result of genetic differences in
P-gp and other transporters.

 

‘
‘x  ‘  ‘
‘x‘
‘

Drug absorption may be affected by any disease that causes changes in (1) intestinal blood flow,
(2) gastrointestinal motility, (3) changes in stomach emptying time, (4) gastric pH that affects
drug solubility, (5) intestinal pH that affects the extent of ionization, (6) the permeability of the
gut wall, (7) bile secretion, (8) digestive enzyme secretion, or (9) alteration of normal GI flora.
Some factors may dominate, while other factors sometimes cancel the effects of each other.
Pharmacokinetic studies comparing subjects with and without the disease are generally necessary
to establish the effect of the disease on drug absorption. Several clinical examples are given
below.

Patients in an advanced stage of 
 

‘  may have difficulty swallowing and
greatly diminished gastrointestinal motility. A case was reported in which the patient could not
be controlled with regular oral levodopa medication because of poor absorption. Infusion of oral
levodopa solution using a j-tube gave adequate control of his symptoms. The patient was
subsequently placed on this mode of therapy.

‘‘‘‘‘‘‘‘‘~
‘ ‘
‘
 ‘ 
‘(imiprimine, amitriptyline, and nortriptyline) and
antipsychotic drugs (phenothiazines) with anticholinergic side effects may have reduced
gastrointestinal motility or even intestinal obstructions. Delays in drug absorption, especially
with slow-release products, have occurred.

‘‘‘‘‘‘‘‘‘‘‘


 ‘may not have adequate production of acids in the stomach; stomach
HCl is essential for solubilizing insoluble free bases. Many weak-base drugs that cannot form


soluble salts will remain undissolved in the stomach when there is no hydrochloric acid present
and are therefore unabsorbed. Salt forms of these drugs cannot be prepared because the free base
readily precipitates out due to the weak basicity.

Dapsone, itraconazole, and ketoconazole may also be less well absorbed in the presence
of achlorhydria. In patients with acid reflux disorders, proton pump inhibitors, such as
omeprazole, render the stomach achlorhydric, which may also affect drug absorption. Co-
administering orange juice, colas, or other acidic beverages can facilitate the absorption of some
medications requiring an acidic environment.

‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘ ‘are prone to a number of gastrointestinal (GI) disturbances, such as

increased gastric transit time, diarrhea, and achlorhydria. Rapid gastric transit time and diarrhea
can alter the absorption of orally administered drugs. Achlorhydria may or may not decrease
absorption, depending on the acidity needed for absorption of a specific drug. Indinavir, for
example, requires a normal acidic environment for absorption. The therapeutic window of
indinavir is extremely narrow, so optimal serum concentrations are critical for this drug to be
efficacious.

Drugs that Affect Absorption of Other Drugsë

Anticholinergic drugs in general may reduce stomach acid secretion. Propantheline bromide is an
anticholinergic drug that may slow stomach emptying and motility of the small intestine.
Tricyclic antidepressants and phenothiazines also have anticholinergic side effects that may
cause slower peristalsis in the GI tract. Slower stomach emptying may cause delay in drug
absorption.

‘‘‘‘‘‘‘‘‘  Metoclopramide is a drug that stimulates stomach contraction, relaxes the pyloric
sphincter, and, in general, increases intestinal peristalsis, which may reduce the effective time for
the absorption of some drugs and thereby reduce the peak drug concentration and the time to
reach peak drug concentration. For example, digoxin absorption from a tablet is reduced by
metoclopramide but increased by an anticholinergic drug, such as propantheline bromide.

Œ
Allowing more time in the stomach for the tablet to dissolve generally helps with the dissolution
and absorption of a poorly soluble drug, but would not be helpful for a drug that is not soluble in
stomach acid.

‘‘‘‘‘‘‘‘‘‘  Antacids should not be given with cimetidine, because antacids may reduce drug
absorption. Antacids containing aluminum, calcium, or magnesium may complex with drugs
such as tetracycline, ciprofloxacin, and indinavir, resulting in a decrease in drug absorption. To
avoid this interaction, antacids should be taken 2 hours before or 6 hours after drug
administration. As mentioned, proton pump inhibitors, such as omeprazole, render the stomach
achlorhydric, which may also affect drug absorption.

 u 
 
‘



The GIT is extensively supplied by blood capillary network and lymphatic system. The absorbed
drug can thus be taken up by the blood or the lymph. Since the blood flow rate to the GIT is 500-
1000 times more than the lymph flow, most of the drugs reach systemic circulation via blood.
Whereas few drugs which have low molecular weight, lipid soluble compounds are removed by
lymphatic system.

The high perfusion rate of GIT ensures that once the drug has crossed the membrane, it
is rapidly removed from the absorption site thus maintaining the sink conditions and
concentration gradient for continued drug absorption. For drugs having high permeation rates
like highly lipid soluble drugs or drugs absorbed through pores, the GI perfusion rate could be a
rate limiting step in the absorption. But in case of poorly permeable drugs blood flow is also
important for actively absorbed drugs since oxygen and energy is required for transportation.

Gastrointestinal contentsë‘a number of GI contents can influence drug absorption.

The effect a drug has on a person may be different than expected because that drug interacts with

‘ Another drug the person is taking (drug-drug interaction)

[
 ‘ Food, beverages, or supplements the person is consuming (drug-nutrient interaction)
‘ Another disease the person has (drug-disease interaction).

The effects of drug interactions are usually unwanted and sometimes harmful. Interactions may
increase or decrease the actions of one or more drugs, resulting in side effects or failed treatment.
Pregnancy may have an effect on the absorption of some drugs. During pregnancy, peristalisis
and gastric emptying are slowed down. And secretion of gastric increases which affects
absorption of acidic drugs.

x$

‘
  
‘

Nutrients include food, beverages (including alcohol), and dietary supplements. Consumption of
these substances may alter the effects of drugs the person takes.

Food like drugs taken by mouth must be absorbed through the lining of the stomach or the
small intestine. Consequently, the presence of food in the digestive tract may reduce absorption
of a drug. Often, such interactions can be avoided by taking the drug 1 hour before or 2 hours
after eating.

Dietary Supplementsë Dietary supplements, including medicinal herbs, are products

(besides tobacco) that contain a vitamin, mineral, herb, or amino acid and that are intended as a
supplement are regulated as foods, not as drugs, so they are not tested as comprehensively.
However, they may interact with prescription or over-the-counter drugs. People who take dietary
supplements should tell their doctors and pharmacists, so that interactions can be avoided.

1.Alcoholë Although many people do not consider alcohol a nutrient, it affects body processes
and interacts with many drugs. For example, taking alcohol with the antibiotic metronidazole
Some Trade Names. presence of food may delay, reduce, increase or may not effect drug
absorption. This type of interaction is due to the influence of food on physiological functions or
consequence of physicochemical interaction with the drug. As a general rule drugs are better
absorbed under fasting conditions and presence of food retards or prevent it.

r
Specific meal components also have an influence on drug absorption. Meals high in fat aid
solubilisation of poorly aqueous soluble drugs. Food high in protein inhibits absorption of
levodopa.

x$x
  
‘

Drug-drug interactions can involve prescription or nonprescription (over-the-counter) drugs.

Types of drug-drug interactions include duplication, opposition (antagonism), and alteration of
what the body does to one or both drugs.

Physicochemical drug-drug interaction ±

Adsorption- antidiarrhoeal preparation containing adsorbents like kaolin/pectin retards or

prevents absorption of number of drugs co-administered with them.

Complexation- antacids and mineral substitute containing heavy metals such as aluminium, iron,
calcium retards the absorption of tetracycline¶s through formation of unabsorbable compounds.

Physiological drug-drug interaction‘%‘‘

Decreased GI transit- anticholinergics such as propantheline retards the GI motility and promotes
absorption of drugs like ranitidine and dioxins, whereas delay of absorption of paracetomol and
sulphamethoxazole.

Increased gastric emptying ± metoclopromide promotes GI motility and enhances absorption of

tetracycline, levadopa.

1.Fluid volumeë‘administration of drug with large volume of fluid results in better dissolution,
rapid gastric emptying and enhanced absorption. Erythromycin is better when taken with glass of
water under fasting conditions.

]
   ‘  &‘
‘ ‘  

There are three main reason for decreased bioavailability of orally absorbed drugs they are
decreased absorption, destabilization, first pass metabolism.

Before a drug reaches blood circulation, it has to pass first time through organs of elimination
like GIT, liver. The loss of drug through biotransformation by such eliminating organs during its
passage through systemic circulation is called as first pass metabolism. The diminished drug
concentrations are rarely, complete absence of the drug in plasma after oral administration is
indicative of first pass effects. The three primary systems which effect presystemic metabolism
of drug are

1. Luminal enzyme- the metabolism by these enzymes are further categorized into two they
are digestive enzymes, Bacterial enzymes.

2. Gut wall enzymes

3. Hepatic enzymes

a)Digestive enzymes

These are the enzymes present in the gut fluids and include enzymes from intestinal and
pancreatic secretions. The latter contains hydrolases which hydrolyse ester drugs like
chloramphenicol palmitate into active chloramphenicol, and peptidases which split amide
linkages and inactivate protein/polypeptide drugs. Thus, one of the approaches to effect oral
absorption of peptides is to deliver them to colon which lack peptidases.

b)Bacterial enzymesë

The GI microflora is scantily present in stomach and small intestine and is rich in colon. Hence,
most orally administered drugs remain unaffected by them. The colonic microbes generally
render a drug more active or toxic on biotransformation ±sulphasalazine, a drug used in
ulcerative colitis, is hydrolysed to sulphapyridine and 5-amino salicylic acid by the microbial
enzymes of the colon. An important role of intestinal microflora is that in enterohepatic cycling.
è
Their enzymes hydrolyse the conjugates of drugs actively secreted via bile such as glucuronides
of digoxin and oral contraceptives. The free drugs are reabsorbed into the systemic circulation.

2 ‘ u‘  ‘
' ‘ also called as mucosal enzymes, they are present in the stomach,
intestine and colon. Alcohol dehydrogenase(ADH) is an enzyme of stomach mucosa that
inactivates ethanol. Intestinal mucosa contains both phase I and phase II (predominant) enzymes,
e.g. sulphation of ethinyl oestradiol and isoprenaline. The colonic mucosa also contain both
phase I and phase II enzymes. However, it is only the enzymes of the proximal small intestine
that are most active.

3.‘#  ‘
' 

Several drugs undergo first-pass hepatic metabolism, the highly extracted ones being
isoprenaline, propranolol, alprenolol, pentoxyphylline, nitroglycerine, diltiazem, nifedipine,
lidocaine, morphine.

w
 ½  ½‘

Bioavailability and pharmacological action of the drug mainly affects the drug absorption
although generally drug absorption is resistant to the effects of aging, certain physiologic
changes in GI function. When considering the impact of these changes on treatment of the
elderly patients and children. it is important to realize that the GI tract is not a homogenous,
static organ. For example, while fasting gastric pH is similar in older and younger individuals,
postprandial return to basal levels slows with age. These effects, and many others, could beget
modi¿ed drug solubility, altered transport protein activity, and other consequences that reshape
drug absorption pro¿les among the elderly.

Currently, there is an increased research focus on ADE pharmacokinetics in the elderly,

often centered on changes in drug elimination processes. However, the absorption kinetics of
certain drug products may be substantially affected by age-related changes in GI function as
well.

However, large variation have been found in the way patient respond to the drug thus it
is important that the drug absorption mainly depends on different factors like physiological,
pharmaceutical and physicochemical factors and while preparing the dosage forms all the
parameters for effective drug absorption are to be considered for better and effective clinical
trials to produce reliable therapeutic effects and thereby reducing the patient compliance.

Õ
‘

½‘

1 D.M.Brahmankar, sunil.B.jaiswal Biopharmaceutics and Pharmacokinetics- treatise(2nd

edition)2009

2.Milo gibaldi, Biopharmaceutics and clinical pharmacokinetics,(4th edition)2008

3 Shargel,L.; Yu, A.B. (1999).  ‘


Ú ‘ ‘ 
Ú
   (4th ed.). New
Yorkë McGraw-Hill.

4.Griffin, J.P. The Textbook of Pharmaceutical Medicine (6th Ed.). New Jerseyë BMJ Books.

5 Heaney RP (2001). "Factors Influencing the Measurement of Bioavailability, Taking Calcium

as a Model". ´ ‘!
cc (4 Suppl)ë

6 Srinivasan VS (2001). "Bioavailability of Nutrientsë A Practical Approach to In Vitro

Demonstration of the Availability of Nutrients in Multivitamin-Mineral Combination
Products". ´ ‘!
cc (4 Suppl)ë 1349S-1350S.

7.www.scribd.com/doc/26776869/factors affecting inter individual varioaton in drug response

8.www.healthandage.com/html/min/eama/eamat/idx/docs/teachers_lectures/ritz/phadyn_elderly_
3.pdf

9.www.pubmed.com/doc/factors affecting drug absorption/2.pdf

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