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D
Department of Pharmaceutics
KLE Universitys College of Pharmacy
BELGAUm 590010, Karnataka, India
Cell No: 00919742431000
E-mail: bknanjwade@yahoo.co.in
08/10/2010 KLECOP, Nipani 1
CONTENTS
Introduction of absorption.
Structure of the Cell Membrane.
Gastro intestinal absorption of drugs.
Mechanism of Drug absorption.
Factors affecting drug absorption
Absorption of drugs from non-per oral routes
Methods of determining absorption
References.
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Introduction of Absorption
Definition :
The process of movement of unchanged
drug from the site of administration to systemic
circulation.
Time
1) Phospholipids :
Principal type of lipid in
membrane about 75 %.
Contains polar and non polar
region.
Polar region is hydrophilic and
non polar region is hydrophobic.
Non polar head contain two fatty
acid chain.
One chain is straight fatty acid
chain.( Saturated )
Another tail have cis double bond
and have kink in tail.
( Unsaturated )
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CHOLESTEROL
Amount in membrane is 20 %.
Insert in membrane with same orientation as
phospholipids molecules.
Polar head of cholesterol is aligned with polar head of
phospholipids.
FUNCTION:
Immobilize first few hydrocarbons groups
phospholipids molecules.
Prevents crystallization of hydrocarbons &
phase shift in membrane
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OH
FUNCTIONS:
Protective
Insulator
Site of receptor binding
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COMPOSITION OF PROTEINS
PROTEINS
LIPID
INTEGRAL PERIPHERAL
ANCHORED
PROTEINS PROTEINS
PROTEINS
Ex. G Proteins.
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PERIPHERAL PROTEINS
Attached to integral membrane proteins OR
associated with peripheral regions of lipid bilayer.
dQ = D A Km/w (CGIT C)
dt h
dc = N. R2. A . C
dt () (h)
where,
dc = rate of the absorption.
dt
N = number of pores
R = radius of pores
C = concentration gradient
= viscosity of fluid in the pores
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3) CARRIER MEDIATED
TRANSPORT MECHANISM
Involves a carrier (a component of the membrane)
which binds reversibly with the solute molecules to be
transported to yield the carrier solute complex which
transverses across the membrane to the other side
where it dissociates to yield the solute molecule
The carrier then returns to its original site to accept a
fresh molecule of solute.
There are two types of carrier mediated transport
system:
a) facilitated diffusion
b) active transport
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a) Facilitated diffusion
In this system, no
expenditure of energy is
involved (down-hill
transport), therefore the
process is not inhibited by
metabolic poisons that
interfere with energy
production.
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Limited importance in the absorption of drugs.
e.g. Such a transport system include entry of glucose
into RBCs & intestinal absorption of vitamins B1 &
B2.
A classical example of passive facilitated diffusion is
the gastro-intestinal absorption of vitamin B12.
An intrinsic factor (IF), a glycoprotein produced by
the gastric parietal cells, forms a complex with
vitamin B12 which is then transported across the
intestinal membrane by a carrier system.
It is another
mechanism is
able to explain
the absorption of
such drugs
which ionize at
all pH condition.
A) Phagocytosis
B) Pinocytosis
C) Transcytosis
This process is
important in the
absorption of oil
soluble vitamins & in
the uptake of
nutrients.
The ultimate goal is to have the drug reach the site of action in
a concentration which produces a pharmacological effect. No
matter how the drug is given (other than IV) it must pass
through a number of biological membranes before it reaches
the site of action.
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Rate dependent on polarity and size.
The greater the lipid solubility the faster the rate of diffusion
PHYSIOLOGICAL FACTORS:
Gastrointestinal (Gi) Physiology
Influence Of Drug Pka And Gi Ph On Drug Absorbtion
Git Blood Flow
Gastric Emptying
Disease States
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PENETRATION OF DRUGS THROUGH
GASTRO-INTESTINAL TRACT
The Git barrier that separates the lumen of the stomach and intestine
from systemic circulation and is composed of lipids, proteins and
polysaccharides.
1. Passive diffusion
2. Pore transport
3. Facilitated transport
4. Active transport
5. Pinocytosis
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1. PASSIVE DIFFUSION
Major process for absorption of more than 90% of drugs
Diffusion follows Ficks law:
The drug molecules diffuse from a region of higher
The stratum corneum is the outermost layer of the epidermis and is composed
mainly of dead keratinised cells (from lack of oxygen and nutrients). It has a
thickness between 10 - 40 m.
The dermis is the layer of skin beneath the epidermis. It contains the hair
follicles, sweat glands, sebaceous glands, apocrine glands, lymphatic vessels
and blood vessels.
Hypodermis - Its purpose is to attach the skin to underlying bone and muscle
as well as supplying it with blood vessels and nerves. The main cell types are
fibroblasts, macrophages and adipocytes (the hypodermis contains 50% of
body fat).
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ROUTES OF PENETRATION
Through follicular region
Through sweat ducts
Through unbroken stratum corneum
Thus, lipid soluble drugs can easily penetrate by diffusion and smaller
drug molecules can penetrate by pore transport.
All these factors make intestine the best site for absorbtion of most drugs.
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INFLUENCE OF DRUG pKa AND GI PH ON
DRUG ABSORBTION
Drugs Site of absorption
Very weak acids (pKa > 8.0) Unionized at all ph values
Absorbed along entire length of GIT
Moderately weak acids (pKa 2.5 7.5) Unionized in gastric ph
Ionized in intestinal ph
Better absorbed from stomach
Strong acids (pKa <2.5) Ionized at all ph values
Poorly absorbed from git
Very weak bases (pKa < 5) Unionized at all ph values
Absorbed along entire length of GIT
Moderately weak bases (pKa 5 11 ) Ionized in gastric ph
Unionized in intestinal ph
Better absorbed from intestine
Strong bases (pKa >11) Ionized at all ph values
Poorly Absorbed from GIT
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GIT BLOOD FLOW
The absorption of lipid soluble drugs and molecules that are small
enough to easily penetrate through Aq. pores is rapid and highly
dependent on rate of blood flow
Body Position Lying on the left side decreases emptying rate and right
side promotes it
Git PH Retarded at low stomach PH and promoted at higher
alkaline PH
Emotional state Anxiety promotes where as depression retards it
Disease states gastric ulcer, hypothyroidism retards it, while duodenal
ulcer, hyperthyroidism promotes it.
PHYSICAL FACTORS
PHYSIO-CHEMICAL FACTORS
This study is imp. for drugs that have low aqueous solubility.
Absorption of such drugs can be increased by increasing particle
size by Micronization.
Reasons:
9. Dissolution
Disintegration is the formation of dispersed granules from an
intact solid dosage form whereas the dissolution is the formation
of solvated drug molecules from the drug
DISSOLUTION
DRUG AT ABSORPTION
SITE
ABSORPTION
DRUG IN
SYSTEMIC
CIRCULATION
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NOYES AND WHITNEYS EQUATION
dc/dt = KS(CS-C)
Where,
dc/dt = Rate constant, K = constant, S = surface area
of the dissolving solid, Cs=solubility of the drug in the
solvent, C=concentration of drug in the solvent at time t.
Constant K=D/h
Where, D is the diffusion coefficient of the dissolving
material and h is the thickness of the diffusion layer
Here, C will always negligible compared to Cs
So,
dc/dt=DSCs/h
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P H Y S I C O C H E M I C A L FA C TO R S
Most drugs are either weak acids or weak bases whose degree
of ionization is depend upon pH of biological fluid.
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For a drug to be absorbed, it should be unionized and the
unionized portion should be lipid soluble.
pH solubility profile:
soluble
1)Basic drug 1) Acidic medium( stomach)
2)Acidic drug 2) basic medium( intestestine)
5. Viscosity of suspension
Eg. Methyl cellulose reduces the rate and absorption of
nitrofurantoin
6. Inclusion of colourants:
Eg. Brilliant blue in phenobarbitone suspension.
1.Compressed tablets
2. Coated tablets
A B
Intact tablets a granules primary drug particles
K2
K1 K3
Drug in GI fluid
K4
K3>>K2>>K1
3.Effect of lubricants:
Magnesium stearate will retard the dissolution of aspirin tablet
Whereas SLS enhance the dissolution.
5. Effect of colorants:
SUGAR COATING:
Sugar,Shellac,fatty glycerides, bees wax, silicone resin
Sub coating agent: Talc,acacia,starch.
FILM COATING:
Polymers, dispersible cellulose derivatives like HPMC
CMC.
ENTERIC COATING:
Shellac, cellulose acetate phthalate etc.
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Factors affecting the drug release are
1.Thickness of coating
e.g.. Quinine shows decrease in rate of absorption
if coated with cellulose acetate phthalate.
3.Effect of ageing:
e.g. The shellac coated tablets of Para amino salicylic
acid when given after two years plasma concentration
of 6-7mg/100ml. However the tablets stored for 3 years
showed plasma concentration of only 2mg/100ml which is
the sub therapeutic effect.
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SUBLINGUAL / BUCCAL ROUTE
SUBLINGUAL ROUTE: the dosage form is placed
beneath the tongue.
BUCCAL ROUTE: Dosage form is placed between
the cheek and teeth or In the cheek pouch.
Drugs administered by this route are supposed to
produce systemic drug effects, and consequently, they
must have good absorption from oral mucosa.
Oral mucosal regions are highly vascularised
therefore rapid onset of action is observed.
For Eg, anti-anginal drug Nitroglycerin.
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SUBLINGUAL / BUCCAL ROUTE
Dermis
Water - 98%
Solid -1.8%
Organic element
Protein - 0.67%, sugar - 0.65%, Nacl - 0.66%
Circulation technique.
Mucosal side
(intestinal segment before eversion)
Serosal side
Buffer solution
Ligature
Mucosal side
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(after eversion)
Advantages
Prolongs the viability & integrity of the
preparation after removal from the animal.
Convenience & accuracy with respect to drug
analysis.
The epithelial cells of the mucosal surface are
exposed directly to the oxygenated mucosal
fluid.
Buffer solution
with drug
Water
maintained at
aerator
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(FIG: EVERTED SAC MODIFICATION)
Procedure
Animal fasted for 20-24hrs
Perfusion technique.
Animal anesthetized, a
midline abdominal incision
is made.
Contd..
Replacement of intestinal loop.
Advantages
Simple & reproducible.
Direct method.
Indirect method.
Intestinal motility.
d
Log dose
Fka/2.303
x
Duration of response time
Where,
F= bioavailability.
Ka= the absorption rate constant.
d= threshold dose
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REFERENCES
1. Biopharmaceutics & pharmacokinetics by
D.M.Brahmankar & Sunil B. Jaiswal.
2. Biopharmaceutics & pharmacokinetics by
P.L.Madan.
3. Biopharmaceutics & pharmacokinetics by
G.R.Chatwal.
4. Human anatomy & physiology by Tortora.
5. www.google.com.