Drug Absorption from GI Tract

DRUG ABSORPTION FROM
GI TRACT
SILAMBARASAN I
M PHARM(PHARMACEUTICS)
MTPG & RIHS

DEFINITION
■ Drug absorption is defined as process of movement of unchanged drug from the site of
administration to systemic circulation.
■ Effectiveness depends on rate and extent of absorption at particular site.

GI TRACT
 The primary function is secretion, digestion ,and
absorption.
 The mean length of entire GIT is 450 cm.
 It is lined by a thin layer of mucopolysaccharides which
act as an impermeable barrier to particulates such as
bacteria, cells or food particles.

STOMACH
■ Bag like structure having small surface area due to absence of microvilli.
■ Drugs which are acid sensitive must not be in contact with acidic environment of the
stomach.
■ Gastric residence time is limited due to which there is limited opportunity for gastric
uptake of drug.

SMALL INTESTINE
It is the major site for absorption of most drugs due to its special characteristics:
 Large surface area
 Great length of small intestine : results in more than 200sq meters of which is several times that
of stomach.
 Greater blood flow: 6 to 10 times more than stomach
 Favorable pH range: 5-7.5
 Slow peristaltic movement : Prolongs residence time of drugs
 High permeability

LARGE INTESTINE
■ Length and mucosal surface area is very small(Villi & Microvilli is absent) in
comparison to small intestine.
■ Its contents are neutral or alkaline.
■ The main role of large intestine is absorption of water and electrolytes.
■ Surface area :4-5 ft

CELL MEMBRANE STRUCTURE & PHYSIOLOGY
■ Movement of drug across the membrane is called as drug transport.
■ Consists of a double layer of amphiphilic phospholipid molecules.
■ Bimolecular layer of lipids is contained between two parallel monomolecular layers of
proteins(Mayonnaise sandwich).
■ Aqueous filled pores or perforations of 4 to 10 Å in diameter through which small
inorganic ions like Urea can pass.

MECHANISMOF DRUG ABSORPTION
Three broad Categories
1)Transcellular /Intracellular transport
A)Passive transport process
-Passive diffusion
-Pore transport
-Ion pair transport
-Facilitated or mediated diffusion
B)Active transport process
-Primary active transport
-Secondary active transport
2) Paracellular / Intercellular transport
3) Vesicular transport

1)TRANSCELLULAR/INTRACELLULAR TRANSPORT
PROCESS
 It is defined as the passage of drugs across the GI epithelium.
 3 steps involved :
– Permeation of GI epithelial cell membrane
– Movement across the intracellular space (cytosol).
– Permeation of the lateral or basolateral membrane.

A. Passive Transport Processes
 These transport processes do not require energy other than that of molecular motion
(Brownian motion) to pass through the lipid bilayer.
 Passive transport processes can be further classified into following types
– Passive diffusion.
– Pore transport.
– Ion-pair transport.
– Facilitated- or mediated-diffusion.

PASSIVE DIFFUSION
■ Also called non-ionic diffusion.
■ Absorption of more than 90% of the drugs.
■ The driving force is concentration or electrochemical gradient.
■ Passive diffusion is best expressed by Fick’s first law of diffusion.
 
C
-
C
h
DAK
dt
dQ
GIT
m/w

dQ/dt = rate of drug diffusion
D = diffusion coefficient of the drug
A = surface area of the absorbing membrane
Km/w = partition coefficient of the drug between membrane and the
aqueous phase
(CGIT – C) = difference in the concentration of drug in GI fluid & the plasma
h = thickness of the membrane (length)

PORE TRANSPORT
■ It is also called as convective transport, bulk flow or
filtration.
■ The driving force is hydrostatic pressure or the osmotic
pressure differences across the membrane.
■ The process is important in the absorption of low molecular
weight (less than 100), generally water-soluble drugs through
narrow, aqueous-filled channels ex: urea, water and sugars.
■ Chain-like or linear compounds of molecular weight up to
400 Daltons can be absorbed by filtration.
■ Drug permeation through water-filled channels is importance
in renal excretion, removal of drug from the cerebrospinal
fluid and entry of drugs into the liver.

ION-PAIR TRANSPORT
■ Absorption of drugs like quaternary ammonium compounds and sulphonic acids,
which ionise under all pH conditions, is ion-pair transport.
■ Despite their low o/w partition coefficient values, such agents penetrate the membrane
by forming reversible neutral complexes with endogenous ions of the GIT like mucin.
■ Such neutral complexes have both the required lipophilicity as well as aqueous solubility
for passive diffusion. Such a phenomenon is called as ion-pair transport.
■ Propranolol, a basic drug that forms an ion pair with oleic acid, is absorbed by this
mechanism.

Ion-pair transport of a cationic drug

CARRIER MEDIATED TRANSPORT
■ The mechanism is involved is carrier that binds reversibly or non-covalently with the
solute molecules to be transported.
■ This 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.
■ Carriers in membranes are proteins (transport proteins) and may be an enzyme or
some other component of the membrane.

FACILITATED DIFFUSION
■ It is a carrier-mediated transport system that operates down the concentration gradient
(downhill transport) but at a much a faster rate than can be accounted by simple
passive diffusion.
■ The driving force is concentration gradient (hence a passive process). Since no
energy expenditure is involved.
Facilitated
diffusion
of
vitamin
B12

B)ACTIVE TRANSPORT PROCESS
■ This transport process requires energy from ATP to move drug molecules from
extracellular to intracellular milieu.
■ These are of two types
– Primary active transport
– Secondary active transport
■ Symport (co-transport)
■ Antiport (counter-transport)

Primaryactivetransport
 In this process, there is direct ATP requirement.
 The process transfers only one ion or molecule and in only one direction, and hence
called as uniporter.
e.g. absorption of glucose.
Secondaryactive transport
 In these processes, there is no direct requirement of ATP i.e. it takes advantage of
previously existing concentration gradient.
 The energy required in transporting an ion aids transport of another ion or molecule
(co-transport or coupled transport) either in the same direction or in the opposite
direction.
Accordingly this process is further subdivided into
 Symport (co-transport) – involves movement of both molecules in the same
direction. e.g. Na+-glucose symporter
 Antiport (counter-transport) –involves movement of molecules in the opposite
direction. e.g. H+ ions using the Na+ gradient in the kidneys.

2)PARACELLULAR/INTERCELLULAR TRANSPORT
 It is defined as the transport of drugs through the junctions between the GI epithelial cells.
 This pathway is of minor importance in drug absorption.
 The two paracellular transport mechanisms involved in drug absorption are
– Permeation through tight junctions of epithelial cells – this process basically occurs
through openings which are little bigger than the aqueous pores.
Eg: Compounds such as insulin and cardiac glycosides
– Persorption – is permeation of drug through temporary openings formed by shedding
of two neighbouring epithelial cells into the lumen.

3)VESICULAR OR CORPUSCULAR
TRANSPORT(ENDOCYTOSIS)
■ It is energy dependent processes but involve transport of substances within vesicles
into a cell.
■ It involves engulfing extracellular materials within a segment of the cell membrane to
form a saccule or a vesicle (hence also called as corpuscular or vesicular transport)
which is then pinched off intracellularly.
■ Eg: cellular uptake of macromolecular nutrients like fats and starch, oil soluble vitamins
like A, D, E and K, water soluble vitamin like B12 and drugs such as insulin.
■ Vesicular transport of drugs can be classed into two categories –
1)Phagocytosis
2)Pinocytosis

PHAGOCYTOSIS (CELL EATING)
■ Adsorptive uptake of solid particulates

PINOCYTOSIS (CELL DRINKING)
 Uptake of fluid solute.
E.g. Sabine polio vaccine (orally administered)

FACTORS AFFECTINGDRUG ABSORPTION AND
BIOAVAILABILTY
A. Physicochemical factors:
1) Drug solubility & dissolution rate
2) Particle size & effective surface area
3) Polymorphism & amorphism
4) Pseudoploymorphism (hydrates/solvates)
5) Salt form of the drug
6) Lipophilicity of the drug
7) pKa of drug & gastrointestinal pH
8) Drug stability

B. Pharmaceutical factors :
1) Disintegration time (tablets/capsules)
2) Dissolution time
3) Manufacturing variables
4) Pharmaceutical ingredients (excipients/adjuvants)
5) Nature & type of dosage form
6) Product age & storage condition

■ Age
■ Gastric emptying time
■ Intestinal transit time
■ Gastrointestinal pH
■ Diseased states
■ Blood flow through the GIT
■ Gastrointestinal contents
- Other drugs
- Food
-Fluids
-Other normal G.I contents
■ Presystemic metabolism by
-Luminal enzymes
-Gut wall enzymes
-Bacterial enzymes
-Hepatic enzymes
C.PATIENT RELATED FACTOR

1) DRUG SOLUBILITY AND DISSOLUTION RATE
■ Rate determining process in the absorption of orally administered drugs are :-
1.Rate of dissolution
2.Rate of drug permeation through the bio membrane
■ Hydrophobic-RDS- Dissolution
Eg:- griseofulvin , spironolactone
■ Hydrophilic-RDS-permeation rate limited
Eg: - cromolyn sodium or neomycin

 The concept of maximum absorbable dose (MAD) is used to correlate drug absorption
with its solubility.
MAD = Ka SGI VGI tr
Ka = Intrinsic absorption rate constant
SGI = Solubility of drug in GI fluid
VGI = volume of GI fluid
tr = residence time of drug in GI
 From these equation we can find the,
- Solubility od drug in GI tract
-Intrinsic absorption rate constant specific to drug in solution

■ Important prerequisite for absorption of drug are,
1)Absolute or intrinsic solubility
-Maximum of solute dissolved in given solvent under standard condition of
temperature ,pressure ,pH.
-It is Static property.
2)Dissolution rate
-Amount of solid substance that goes into solution per unit time under standard
condition of temperature ,pH,solvent composition and constant solid surface area.
-It is dynamic property.

THEORIES OF DISSOLUTION
■ Three Theories:
1. Diffusion layer model / Film theory
2. Danckwert’s model / Penetration or Surface renewal theory
3. Interfacial barrier model / Double barrier or Limited solvation theory

1) DIFFUSION LAYER MODEL
■ It involves two steps :
1. Solution of the solid to form stagnant film or diffusive layer which is saturated with the
drug.
2. Diffusion of the soluble solute from the stagnant layer to the bulk of the solution; this is
rate determining step in drug dissolution.

■ The rate of dissolution is given by Noyes and Whitney:
dC/dt = k (Cs- Cb)
where,
dC/dt = dissolution rate of the drug
k = dissolution rate constant
Cs= concentration of drug in stagnant layer
Cb= concentration of drug in the bulk of the solution at time t

.
■ Nernst and Brunner incorporated Fick’s first law of diffusion and modified the Noyes-
Whitney’s equation to :
dC/dt = DAKw/o (Cs-Cb)
Vh
where,
D = diffusion coefficient of drug
A = surface area of dissolving solid
Kw/o = water/oil partition coefficient of drug
V = volume of dissolution medium
h = thickness of stagnant layer
(Cs – Cb) = conc. gradient for diffusion of drug

Limitation :
■ The Noyes-Whitney’s equation assumes that the surface area of the dissolving solid
remains constant during dissolution, which is practically not possible for dissolving
particles.
■ Hence, dissolution methods that involves use of constant surface area discs are
employed to determine the rate of dissolution.
■ To account for the particle size decreases and change in the surface area accompanying
dissolution, Hixson and Crowell’s cubic root law of dissolution is used:
Wo1/3–W1/3= K.t
where,
W= mass of drug remaining to be dissolved at time t
K = dissolution rate constant
Wo = original mass of the drug

2) DANCKWERT’SMODEL
■ Danckwert takes into account the eddies or packets that are present in the agitated fluid
which reach the solid-liquid interface, absorb the solute by diffusion and carry it into the
bulk of solution.
■ These packets get continuously replaced by new ones and expose to new solid surface
each time, thus the theory is called as surface renewal theory.
■ The Danckwert’s model is expressed by equation:
V. dC/dt= dm/dt = A ( Cs-Cb). √(γ.D)
where,
m = mass of solid dissolved
γ = rate of surface renewal

3) INTERFACIALBARRIERMODEL
 The diffusion layer model and Danckwert’s model were based on two assumptions:
1. The rate determining step that controls dissolution is the mass transport.
2. Solid-solution equilibrium is achieved at the solid/liquid interface.
 According to the interfacial barrier model, an intermediate concentration can exist at
the interface as a result of solvation mechanism and is a function of solubility rather
than diffusion.
 Such a concept is given by the following equation :
G = Ki (Cs-Cb)
where,
G = dissolution rate per unit area
Ki = effective interfacial transport constant

FACTORS AFFECTING DISSOLUTION RATE
1) PHYSICOCHEMICAL PROPERTIES OF
DRUG
-Solubility of drug
-Salt formation
-Particle size
-Polymorphism
2) DRUG PRODUCT FORMULATION
FACTORS
-Diluents
-Disintegrants
-Binders and Granulating agent
-Lubricants
3) PROCESSING FACTORS
-Method of Granulation
-Compression force
-Storage condition
4)FACTORS RELATING DISSOLUTION
APPARTUS & TEST PARAMETERS
-Agitation
-Sampling probe position
-Temperature
-Dissolution medium

DISSOLUTION METHODS
Apparatus are used according to standards specified. The USP includes seven apparatus
design for drug release and dissolution testing of immediate release and for oral dosage
form, for extended release, enteric coated, transdermal drug delivery system.
■ Rotating basket method
■ Paddle method
■ Flow-through method
■ Reciprocating cylinder method
■ Paddle over disk method
■ Rotating cylinder method
■ Reciprocating disk method

2)PARTICLE SIZE & EFFECTIVE
SURFACE AREA
■ Particle size may play a major role in drug absorption.
■ Smaller the particle size, greater the surface area .
■ Particle size reduction has been used to increase the absorption of a large number of
poorly soluble drugs.
E.g. Bishydroxycoumarin, digoxin, griseofulvin
■ Two types of surface area
1) Absolute surface area
2) Effective surface area

■ In absorption studies, the effective surface area is of much important than absolute.
■ To increase the effective surface area, we have to reduce the size of particles up to 0.1
micron. So these can be achieved by “micronisation process’’.
■ Keep in mind that which type of drug is micronized if it is:
a) HYDROPHILIC DRUGS:
In hydrophilic drugs the small particles have higher energy than the bulk of the
solid resulting in an increased interaction with the solvent
b) HYDROPHOBIC DRUGS:
In this micronisation techniques results in decreased effective surface area & thus
fall in dissolution rate.

3) POLYMORPHISM & AMORPHISM
■ Depending upon the internal structure, a solid can exist either in a crystalline or
amorphous form.
■ When a substance exists in more than one crystalline form, the different forms are
designated as polymorphs, and the phenomenon as polymorphism.
 Polymorphs are of two types:
1) Enantiotropic polymorph is the one which can be reversibly changed into another
form by altering the temperature or pressure.E.g. Sulphur.
2) Monotropic polymorph is the one which is unstable at all the temperature or
pressures. E.g. glyceryl stearates.

 AMORPHISM: Some drugs can exist in amorphous form (i.e. having no internal
crystal structure). Such drug represents the highest energy state.
 They have greater aqueous solubility than the crystalline forms because a energy
required to transfer a molecule from the crystal lattice is greater than that required for
non-crystalline (amorphous form).
 For example: the amorphous form of Novobiocin is 10 times more soluble than the
crystalline form.
 Thus, the order of different solid dosage forms of the drugs is
Amorphous > Meta-stable > stable

4) PSEUDOPLOYMORPHISM
 When the solvent molecules are entrapped in the crystalline structure of the
polymorph, it is known as pseudo-polymorphism.
 Solvates: The stoichiometric type of adducts where the solvent molecules are
incorporated in the crystal lattice of the solid are called as the solvates, and the
trapped solvent as solvent of crystallization.
 Hydrates: when the solvent in association with the drug is water , the solvate is known
as a hydrate.
 Hydrates/Solvates are pseudo-polymorphs where hydrates are less soluble and solvates
are more soluble and thus affect the absorption accordingly.
 For example: n-pentanol solvates of fludrocortisone and succinyl-sulfathiazole have
greater aqueous solubility than the non-solvates.

5)SALT FORMOF THE DRUG
While considering the salt form of drug, pH of the diffusion layer is important not the pH
of the bulk of the solution.
 Example of salt of weak acid- It increases the pH of the diffusion layer, which promotes
the solubility and dissolution of a weak acid and absorption is bound to be rapid.
 Other approach to enhance the dissolution and absorption rate of certain drugs is the
formation of in – situ salt formation i.e. increasing in pH of microenvironment of drug
by incorporation of a buffering agent. E.g. aspirin, penicillin
 But sometimes more soluble salt form of drug may result in poor absorption. e.g. sodium
salt of phenobarbitone viz., its tablet swells and did not get disintegrate, thus dissolved
slowly and results in poor absorption.

6 & 7) DRUGpKa AND LIPOPHILICITY ANDGI PH-PARTION
HYPOTHESIS
The theory states that for drug compounds of molecular weight more than 100, which are
primarily transported across the bio-membrane by passive diffusion, the process of
absorption is governed by:
1. The dissociation constant pKa of the drug
2. The lipid solubility of the un-ionized drug
3. The pH at the absorption site

A) DRUGpKa AND GI pH:
 Amount of drug that exists in un-ionized form is a function of pKa of drug and pH of the
fluid at the absorption site.
 The relative amount of ionized and unionized drug in solution at particular pH and the
percent of drug ionized at this pH can be determined by Henderson Hasselbach equation.
For weak acids,
pH = pKa + log [ionized]
[un-ionized]
% Drug ionized = 10pH-pKa x 100
1+10pH-pKa
For weak bases, pH = pKa + log [un-ionized]
[ionized]
% Drug ionized = 10pKa-pH x 100
1+10pKa-pH

 If there is a membrane barrier that separates the aqueous solutions of different pH such
as the GIT and the plasma, then the theoretical ratio R of drug concentration on either
side of the membrane can be given by the following equations:
For weak acids,
Ra = CGIT = 1+10pHGIT-pKa
Cplasma 1+10pHplasma-pKa
For weak bases,
Rb = CGIT = 1+10pKa-pHGIT
Cplasma 1+10pKa-pHplasma

B) LIPOPHILICITY AND DRUGABSORPTION:
 The lipid solubility of the drug is measured by parameter called as log p ,where p is
oil/water partition co-efficient (Ko/w) value, whereby the increase in this value indicates
the increase in percentage drug absorbed.
 Ko/w = Distribution of the drug in the organic phase (octanol)
Distribution of the drug in the aqueous phase
LIMITATION OF pH PARTITION HYPOTHESIES:
 Presence of virtual membrane pH
 Absorption of ionized drug
 Influence of GI surface area and residence time of drug
 Presence of aqueous unstirred diffusion layer

8)DRUG STABILITY
■ A drug for oral use may destabilize either during its shelf life or in the GIT.
■ Two major stability problems resulting in poor bioavailability of an orally
administered drug are
- Degradation of the drug into inactive form
- interaction with one or more different component either of the dosage form or
those present in the GIT to form a complex that is poorly soluble or is absorbable.

B)PHARMCEUTICAL FACTORS
1) DISINTEGRATIONTIME (TABLETS/CAPSULES):
Rapid disintegration is important to have a rapid absorption.
Disintegration time of tablet is directly proportional to amount of binder & Compression
force.
In vitro disintegration test gives no means of a guarantee of drugs bioavailability because
if the disintegrated drug particles do not dissolve then absorption is not possible.
E.g. Coated tablet have long disintegration time.
Fast dispersible tablets have short disintegration time

2) DISSOLUTIONTIME:
Dissolution is a process in which a solid substance solubilizes in a given solvent i. e mass
transfer from the solid surface to the liquid phase.
Dissolution time is also an important factor which affect the drug absorption.
3) MANUFACTURINGVARIABLES:
 Several manufacturing processes influence drug dissolution from solid dosage forms.
 For example: For tablet it is
 Method of granulation
 Compression force

Methodof granulation:
 The wet granulation process is the most conventional technique.
 The tablets that dissolve faster than those made by other granulation methods.
 But wet granulation has several limitations like formation of crystal bridge or chemical
degradation while drying.
 The method of direct compression force has been utilized to yield the tablets that
dissolve at a faster rate.
Compressionforce:
 The compression force employed in tableting process influence density, porosity,
hardness, disintegration time and dissolution rate of tablets.
 Higher compression force increases the density and hardness of the tablet, decreases
porosity and hence penetrability of the solvent into the tablet and thus in slowing of
dissolution and absorption (Fig .A)

On the other hand, higher compression force causes deformation, crushing or fracture
of drug particles into smaller ones and causes a large increase in effective surface area.
This results in an increase in dissolution rate of tablets (Fig B)
A combination of both the curves A and B is also possible as shown in curves C & D.
Fig.Influence of compression force on the dissolution rate of tablets

4) PHARMACEUTICALINGREDIENTS (EXCIPIENTS/ADJUVANTS):
 More the number of Excipients in the dosage form, more complex it is & greater the
potential for absorption and Bioavailability problems.
 Commonly used excipients in various dosage forms are,
A) VEHICLE:
 Major component of liquid oral and parenteral.
 Rate of absorption – depends on its miscibility with biological fluid.
 Miscible vehicles causes rapid absorption e.g. propylene glycol.
 Immiscible vehicles – Absorption depends on its partitioning from oil phase to aqueous
body fluid.

B) DILUENTS:
 Used to produce the necessary bulk.
 Hydrophilic diluents – Imparts Absorption
Hydrophobic diluents – Retards Absorption
 Also, there is a drug-diluent interaction, forming insoluble complex and retards the
absorption. E.g. Tetracycline-DCP
C) BINDERS& GRANULATINGAGENT:
 Used to hold the particles together to form granules .
 Hydrophilic binders – Imparts hydrophilic properties to the granule surface – gives better
dissolution properties. E.g. Starch,Gelatin. PVP.
 More amount of binder increases the hardness of the tablet and retards the absorption rate.

D) DISINTEGRANTS:
 Mostly hydrophilic in nature.
 Decrease in amount of disintegrants – significantly lowers bioavailability.
Eg: Microcrystalline cellulose
E) LUBRICANTS:
 These agent added to tablets formulation to aid flow of granules ,to reduce interparticle
friction and adhesion of particles to dies and punches.
 Commonly hydrophobic in nature – therefore inhibits penetration of water into tablet
and thus dissolution and disintegration.

F) SUSPENDINGAGENTS/VISCOSITYAGENT
 Stabilized the solid drug particles by reducing the rate of settling through an increase in
the viscosity of medium.
 Macromolecular gum forms un-absorbable complex with drug
e.g. Na CMC form poor soluble complex with amphetamine.
 Viscosity imparters – act as a mechanical barrier to diffusion of drug from its dosage
form and retard GI transit of drug.
G) SURFACTANTS
 May enhance or retards drug absorption by interacting with drug or membrane or both.
 e.g. Griseofulvin, steroids
 It may decrease absorption when it forms the un-absorbable complex with drug above
CMC.

H) BUFFERS:
 Buffers are sometimes useful in creating the right atmosphere for drug dissolution as was
observed for buffered aspirin tablets.
 However, certain buffer systems containing potassium cations inhibit the drug absorption
as seen with Vitamin B2 and sulfanilamide.
I) Colorants:
 Even a low concentration of water soluble dye can have an inhibitory effect on dissolution
rate.
 The dye molecules get absorbed onto the crystal faces and inhibit the drug dissolution.
 For example: Brilliant blue retards dissolution of sulfathiazole.

J) COMPLEXINGAGENTS:
 Complex formation has been used to alter the physicochemical & biopharmaceutical
properties of a drug.
Example
1)Enhanced dissolution through formation of a soluble complex.
E.g. ergotamine tartarate-caffeine complex & hydroquinone-digoxin complex.
2)Enhanced lipophilicity for better membrane permeability.
E.g. caffeine-PABA complex.

5) NATURE & TYPE OF DOSAGE FORM:
 Apart from the proper selection of the drug, clinical success often depends to a great
extent on the proper selection of the dosage form of that drug.
 As a general rule, the bio-availability of a drug form various dosage forms decrease in
the following order:
Solutions > Emulsions > Suspensions > Capsules > Tablets > Coated Tablets > Enteric
Coated Tablets > Sustained Release Products.

6) PRODUCT AGE & STORAGE CONDITION
■ Product aging and storage conditions can adversely affect the bio-availability by change
in especially the physico-chemical properties of the dosage forms.
For example:
■ Precipitation of the drug in solution
■ Hardening of tablet
■ Change in particle size of suspension.

C)PATIENT RELATED FACTOR
1) AGE
■ In infants, the gastric pH is high and intestinal surface and blood flow to the GIT is
low,resulting in altered absorption pattern in comparison to adults.
■ In elderly persons, causes of impaired drug absorption include altered gastric emptying,
decreased intestinal surface area and GI blood flow, higher incidents of achlorhydria
and bacterial over growth in small intestine.

2) GASTRICEMPTYINGAND MOTILITY
 The passage from stomach to small intestine called as gastric emptying.
Several parameters are used to quantify gastric emptying such as:
Gastric emptying rate:
■ which is the speed at which the stomach contents empty into the intestine.
Gastric emptying time:
■ which is the time required for the gastric contents to the SMALL INTESTINE.
Gastric emptying half-life:
■ which is the time taken for half the stomach contents to empty.

3) INTESTINALTRANSIT
■ Small intestinal is the major site of absorption of most of drugs, long intestinal transit
time is desirable for complete absorption of drugs.
■ It is influenced by various factors such as food, diseases and drugs.
■ Transit time for contents from different regions of intestine
Intestinal region Transit time
Duodenum 5 minutes
Jejunum 2 hours
Ileum 3 to 6 hours
Caecum 0.5 to 1 hour
Colon 6 to 12 hours

4) GASTROINTESTINAL PH
GI fluid pH affect in several ways:
■ Disintegration: The Disintegration of some drugs is pH sensitive with enteric
coating the coat dissolves in only the intestine at specific PH.
■ Dissolution : A large no of drugs whose solubility is greatly affected by pH are
either weak acids or weak bases.
 Stability: GI pH also affect the chemical stability of drugs .
Eg: the acidic stomach pH gives a degradation of penicillin G and erythromycin.
So such drugs to be formulated by preparing prodrugs.

5) DISEASES
A) Gastric diseases:
■ The influence of achlorhydria (decreased gastric acid secretion and increases stomach
pH) on gastric emptying and drug absorption, especially that of acidic drugs (decreased
absorption e.g. aspirin) has been studied.
B) Intestinal diseases:
■ Two of the intestinal disorders related with malabsorption syndrome that influence
drug availability are Celiac disease and Chron’s disease.
C) Cardio-vascular diseases:
■ Several changes associated with congestive cardiac failure influence bio-availability of a
drug viz., oedema of the intestine, decreased blood flow to the GIT and gastric emptying
rate and altered GI pH, secretions and microbial flora.
D) Hepatic diseases:
■ Disorders such as hepatic cirrhosis influence bio-availability mainly of drugs that
undergo considerable first-pass hepatic metabolism e.g. propranolol

6) BLOODFLOW THROUGH GIT:
■ The GIT is extensively supplied by blood capillary network and blood flow rate to GIT
(splanchnic circulation) is 28% of the cardiac output.
■ Therefore, it helps in maintaining sink conditions and concentration gradient for drug
absorption by rapidly removing drug from the site of action.
■ Table : Influence of blood flow effect on various types of drugs
DRUGS BLOOD FLOW EFFECT
■ A) For highly lipid soluble drugs More
■ B) For many lipophilic drugs
such as ethanol, glycerol, etc. Intermediate
■ C) Polar compounds such as ribitol Less

7) GASTROINTESTINAL CONTENTS:
■ Food - drug interactions : presence of food will affect absorption in following way
a) Delay absorption :ex. Aspirin , paracetamol , diclofenac , nitrofurantoin ,digoxin etc.
b) Decreased absorption : ex. Penicillin, erythromycin, ethanol, tetracycline, levodopa etc.
c) Increased absorption : griseofulvin, diazepam, vitamins etc.
d) In some cases it do not affect : methyldopa, propylthiouracil etc.
■ Fluid volume : administration of a drug with large fluid volume results in better
dissolution , rapid gastric emptying and enhanced absorption-
Eg. erythromycin is better absorbed when taken with a glass of water under fasting
condition than when taken with meals.

■ Interaction of drug with normal GI constituents : The GIT contains a number of
normal constituents such as mucin –which is a protective mucopolysaccharides that lines
the GI mucosa , interact with streptomycin.
■ Bile salts- which affect the absorption of lipid soluble drugs like grieseofulvin and
vitamins.
■ Drug-drug interactions : They can either be physiological or physiochemical.

8) Pre-systemicmetabolism
■ For a drug administered orally, the 2 main reasons for its decreased bio-availability
are:
1. Decreased absorption
2. First-pass/pre-systemic metabolism
The four primary systems which affect the pre-systemic metabolism of a drug
■ Lumenal Enzymes
■ Gut wall enzymes/mucosal enzymes
■ Bacterial enzymes
■ Hepatic enzymes.

ROLE OF DOSAGE FORM
SOLUTIONS:
■ Solutions is most rapidly absorbed
■ Drug dissolution is absent
■ Factors influencing absorption of solution are:
-Viscosity
-Surfactants
-Solubilizes
-Stabilizers
-Stability

SUSPENSION
■ Drug dissolution which is generally rapid due to the large surface area of the particles
■ Factors affecting absorption
-Particle size
-Polymorphism
-Wetting agents
-Viscosity of the medium
-Suspending agents

CAPSULES
■ Powders & granules are administered in hard gelatin capsules whereas viscous fluids &
oils in soft elastic shells
Factors of importance in case of hard gel-
■ Drug particle size
■ Density
■ Polymorphism
■ Intensity of packing
■ Influence of diluents & excipients

TABLETS
■ Compressed Tablets > Film Coated Tablets > Sugar Coated Tablets > Enteric
Coated Tablets > Sustained Release Products
Factors:
-Effective surface area
-Dissolution
-Deaggregation
-Permeabilty
-ExcipientsAPI

IVIVC-DEFINITION
■ FDA:
A predictive mathematical model describing the relationship between an in vitro
property of dosage form (usually the rate or extent of drug dissolution or release) and a
relevant in vivo response, e.g., plasma drug concentration or amount of drug .
■ USP:
The establishment of a relationship between a biological property or a parameter
derived from a biological property (Cmax, AUC) produced by a dosage form, and a
physicochemical characteristic (in vitro release) of the same dosage form.

LEVELS OF CORRELATION
■ Based on the ability of the correlation to reflect the complete plasma level profile, which
will result from administration of the given dosage form.
1. Level A
2. Level B
3. Level C

Level A :
 Highest category of correlation.
 Linear correlation.
 Represents point to point correlation between in vitro dissolution time course and in
vivo response time course.
 The major advantage of a Level A correlation is that a point to- point correlation is
developed. All in vitro dissolution data and all in vivo plasma drug concentration–time
profile data are used .
 Once a Level A correlation is established, an in vitro dissolution profile can serve as a
surrogate for in vivo performance.
 A change in manufacturing site, method of manufacture, raw material supplies, minor
formulation modification, and even product strength using the same formulation can be
justified without the need for additional human studies.

LevelB :
■ The mean in vitro dissolution time is compared either to the mean residence time (MRT)
or to the mean in vivo dissolution time.
■ Uses the principles of statistical moment analysis.
■ Is not a point-to-point correlation.
■ Reason - because a number of different in vivo curves will produce similar mean
residence time values.
■ Level B correlations are rarely seen in NDAs.

LevelC :
■ A Level C correlation is not a point-to-point correlation.
■ A Level C correlation establishes a single-point relationship between a dissolution
parameter such as percent dissolved at a given time and a pharmacokinetic parameter of
interest such as AUC and Cmax.
■ Level C correlation is useful for formulation selection and development but has limited
application .
■ Several examples of Level C correlation are given below.
1. Dissolution rate versus absorption rate.
2. Percent of drug dissolved versus percent of drug absorbed.
3. Maximum plasma concentrations versus percent of drug dissolved in vitro.
4. Serum drug concentration versus percent of drug dissolved.

COMPARISON OF PROFILES
In vivo Data
■ Plasma concentration time profile.
■ Pharmacokinetic parameters.
■ Percent drug absorbed time profile.
■ Statistical movement analysis.
In vitro Data
■ Percent drug dissolution profile.
■ Kinetic parameters.
■ Percent drug dissolved time profile.
■ Statistical movement analysis.

Tight junctioncomplex
 Tight junction also known as occluding junction.
 Tight junction are composed of branching network of sealing strands, each strand
acting independently from the other.
 The function of tight junction is to hold the cell together & also the tight junction are
help to maintain the polarity of cell by preventing the lateral diffusion of integral
membrane protein between apical and lateral/basal surface.

REFERENCES
■ Biopharmaceutics and pharmacokinetics by D M BRAHMANKAR

Drug Absorption from GI Tract

Drug Absorption from GI Tract

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