DRUG ABSORPTION FROM THE GASTROINTESTINAL TRACT
TOPIC : GI tract, Mechanism of drug absorption,Factors affecting passive drug
absorption, pH partition theory of drug absorbtion.
I M Pharma
Department of Pharmaceutics
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Drug Absorption
Definition:
❑ The process of movement of unchanged drug from the site of
administration to systemic circulation.
There always exist a correlation between the plasma
concentration of a drug and the therapeutic response.
So absorption can also be defined as the process of
movement of unchanged drug from the site of
administration to the site of measurement i.e. Plasma
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Gastrointestinal tract
The GI tract is an organ system within humans and other animals which takes
in food, digests it to extract and absorb nutrients and energy and expels the
remaining waste.
The human gastrointestinal tract consists of the esophagus , stomach,
intestine and is divided into upper and lower gastrointestinal tract
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STOMACH : The stomach is a bag like structure having a smooth mucosa.
Its acidic pH, due to secretion of HCl favours absorption of acidic drugs.
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• SMALL INTESTINE- It is the major site for absorption of most drugs due to
its large surface area. The surface consists of finger like projection called as
villi which increases surface area 30 times.
Large intestine – Its length and mucosal surface area is very small in comparison
to small intestine and thus absorption of drugs from this region is insignificant.
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• Cell membranes are generally thin, approximately 70 to 100 A in thickness.
• The plasma membrane to be composed of two layers of phospholipids 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.
• Lipid-soluble drugs tend to penetrate cell membranes more easily than polar molecules.
• Proteins provide a pathway for the selective transfer of certain polar molecules and charged
ions through the lipid barrier.
• 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.
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Mechanism of drug absorption
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Mechanism of drug absorption
A. Transcellular/intracellular transport
1.Passive transport process
a. Passive diffusion
b. Pore transport
c. Ion-pair transport
d. Facilitated or carrier mediated diffusion
2. Active transport process
a. Primary active transport
b. Secondary active transport: Symport (co-transport) and
Antiport (counter-transport)
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B. Paracellular/Intercellular Transport:
1. Permeation through tight junctions of
epithelial cells.
2. Persorption
C. Vesicular or corpuscular Transport
(Endocytosis):
1. Pinocytosis
2.Phagocytosis
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A. Transcellular /intracellular Transport:
Passage of drugs across the GI epithelium.
1. Passive Transport process:
do not require energy other than that of molecular motion
(Brownian motion) to pass through the lipid bilayer.
a. Passive diffusion:
Also called as Non-ionic diffusion.
Major process for absorption of more than 90% of the
drugs. Driving force: concentration or electrochemical gradient.
It is defined as the difference in the drug concentration on
either side of the membrane.
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• No energy source required.
•No carrier is needed.
•Water soluble drug
(ionized or Polar): readily
absorbed via aqueous
channels or pores in the cell
membrane.
•Lipid soluble drug
(nonionized
or non polar):
readily absorbed via cell
membrane itself.
•Depends on lipid
solubility.
•Depends on pka of drugpH
of medium.
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•Passive diffusion is best expressed by Fick’s
first law of diffusion.
•Fick’s first law of diffusion states that 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.
•Mathematically,
Where,
dQ/dt = rate of drug diffusion
D= diffusion coefficient
A= surface area of the absorbing
membrane for drug diffusion
Km/w = Partition coefficient
(Cgit-C) = concentration
gradient
h= thickness of membrane
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Certain characteristics of passive diffusion:
Downhill transport.
Process is energy independent and non saturable.
Greater the surface area & lesser the thickness of the membrane=
faster the diffusion & more rapid the rate of drug absorption from
intestine than from stomach.
Equlibrium is attained when the concentration on either side of the
membrane becomes equal.
Greater the membrane/ water partition coefficient of drug = faster the
absorption
❑ Only non-ionised form is absorbable. The rate of transfer of
unionised species is 3 -4 times the rate for ionised drugs.
❑Weak acids: best absorbed in stomach (Aspirin,Phenobarbitone,
Penicillin V)
Weak bases: best absorbed in intestine (Atropine, Ephedrine,
Chloroquine)
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Pore Transport
• Also known as convective transport, bulk flow
or filtration.
• Important in the absorption of low molecular
weight (less than 100). Low molecular size &
generally water-soluble drugs through narrow,
aqueous filled channels or pores in the
membrane structure.
• E.g. urea, water & sugars.
• The driving force for the passage of the drugs is
the hydrostatic or the osmotic pressure
difference across the membrane.
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c. Ion-pair transport
Transport of drugs like quaternary
ammonium compounds and sulphonic
acids, which ionise under all pH conditions.
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
Propranolol, a basic drug that forms an ion
pair with oleic acid, absorbed by this
mechanism.
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d. Facilitated/carrier mediated transport
Mechanism involves driving force = concentration
gradient
No energy expenditure is involved, the process is not
inhibited by metabolic poisons that interfere with
energy production.
Limited importance in the absorption of drugs. For e.g.
such a transport system include entry of glucose into
RBCs and intestinal absorption of vitamins B1 & B2.
A classic example of passive facilitated diffusion is the
GI absorption of vitamin B12.
An intrinsic factor , a glycoprotein produced by the
gastric parietal cells, forms a complex with vitamin
B12, then transported across the intestinal membrane
by a carrier system.
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Active transport Process Further subdivided into:
a. Primary active transport: direct ATP requirement ( e.g. absorption of glucose); carrier
proteins involved in primary active transport are of 2 types:
Ion transporters: responsible for transporting ions in or out of cells (e.g. ATP driven
ion pump called proton pump implicated in acidification of intracellular
compartments); Organic anion transporter aids absorption of Pravastatin and
Atorvastatin; Organic cation transporter aids absorption of Diphenhydramine.
ATP binding transporters: transport small foreign molecules ( drugs and toxins)
especially out of cells i.e. exsorption e.g. p-glycoprotein; responsible for pumping
hydrophobic drugs like anticancer drugs out of cells. (present in brains)
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b. Secondary active transport: no direct requirement of
ATP (takes advantage of previously existing concentration
gradient)
• Symport (co-transport): involves movement of both molecules in the same
direction e.g. Na+ concentration gradient to move glucose against its
concentration gradient
H+ coupled peptide transporter (PEPT1) implicated in the intestinal absorption
of peptide like drugs such as β-lactam antibiotics.
• Antiport (counter-transport): involves movement of molecules in the
opposite direction e.g. expulsion of H+ ions using the Na+ gradient in the
kidneys.
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B. Paracellular/Intercellular transport
Transport of drugs through the junctions
between the GI epithelial cells.
Paracellular transport mechanisms involved in
drug absorption:
Permeation through tight junctions of
epithelial cells: occurs through openings which are
little bigger than the aqueous pores e.g. insulin,
cardiac glycosides
Persorption: through temporary openings
formed by shedding of 2 neighbouring epithelial
cells into the lumen.
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C. Vesicular/ Corpuscular transport ( Endocytosis):
Involves engulfing extracellular materials within a segment of the
cell membrane to form a saccule or a vesicle which is then picnched-
off intracellularly.
Responsible for the cellular uptake of macromolecular nutrients
like fats & starch, oil soluble vitamins like A, D,E & K, water soluble
vitamin like B12 & drugs like insulin.
Bypass first pass hepatic metabolism
Involves 3 processes: Phagocytosis, Pinocytosis and Transcytosis
Transcytosis: Phenomenon in which an endocytic vesicle is
transferred from one extracellular compartment to another.
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Phagocytosis (cell eating):
Adsorptive uptake of solid particulates, macromolecules
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Pinocytosis (cell drinking):
Uptake of fluid solute.
Orally administered Sabin Polio vaccine, lagre protein molecules, botulism toxin, oil, soluble
vitamins etc absorbed by this mechanism
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pH PARTITION THEORY
The theory states that for drug compounds of molecular weight
greater than 100, which are primarily transported across the
biomembrane by passive diffusion.
The process of absorption is governed by:
1. The dissociation constant (pKa) of the drug.
2. The lipid solubility of the unionized drug (a
function of drug Ko/w).
3. The pH at the absorption site.
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Brodie proposed the partition theory to explain the
influence of GI pH and drug pKa on the extent of drug
transfer or drug absorption.
• pH partition theory of drug absorption is based on the
GIT is a simple lipid barrier to the transport of drugs and
chemicals.
• Accordingly the unionized form of an acid or basic
drug, if sufficient lipid soluble, is absorbed but the
ionized formis not.
• The larger the fraction of drug is in the unionized form
at a specific absorption site, the faster is the absorption.
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DRUG pKa AND GI pH
• The fraction of drug in solution that exist in the unionized form is a
function of both dissociation constant of the drug and the pH of the
solution.
• The dissociation constant is often expressed for both acids and bases
as pKa (the basic logarithm of the acidic dissociation constant).
• It is customary to express the dissociation constants of both acidic
and basic drugs by pKa values.
• The lower the pKa of an acidic drug, the stronger the acid i.e.,
greater the proportion of ionized form at a particular pH. The higher
the pKa of a basic drug, the stronger the base.
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Thus from the knowledge of pKa of the drug and pH
at the absorption site (or biological fluid), the relative
amount of ionized and unionized drug in solution at a
particular pH and the percent of drug in solution at
this pH can be determined by Henderson-Hasselbach
equation,
for an acid:
pka-pH=log(fu/fi)
for a base:
pka-pH=log(fi/fu)
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i.e., for weak acids:
pH=pka+log[IDC/UDC]
%drug ionized=[10pH-pka/1+10pH-pka]*100
For weak bases:
pH=pka+log[UDC/IDC]
%drug ionized=[10pH-pka/1+10pH-pka]*100
When the concentration of ionized drug becomes equal,
the second term of the equation becomes zero (since
log1=0) and thus pH=pka. The pka is the characteristic of
the drug
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A barrier that separates the aqueous solutions of different pH such as GIT and
plasma then the theoretical ratio R of drug concentration on either side of the
membrane can be given by the equation,
For weak acids:
Ra=CGIT/CPlasma=1+10pHGIT-pka/1+10pH plasma-pka
For weak bases:
R=CGIT/Cplasma=1+10pka-pHGIT/1+10pka-pH plasma
pH Range In GIT
• The pH range in GIT from 1-8 that of the stomach is from 1-3 and of the
intestine (from duodenum to colon) 5-8, then certain generalization regarding
ionization and absorption of drugs can be made, as predicted from pH partition
hypothesis.
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LIPOPHILICITY AND DRUG
ABSORPTION
• The GI cell membrane are essentially lipoidal.
Highly lipid soluble drugs are generally
absorbed while decidedly lipid insoluble drugs
are in general poorly absorbed.
• The lipid solubility of a drug is determined
from its oil/water partition coefficient (Ko/w)
value.
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DEVIATIONS FROM pH-PARTITION
THEORY
• The pH-partition theory provides a basic frame work for understanding
drug absorption, but it is an over simplification of a more complex process.
• Theory indicates that the relationship between pH and permeation or
absorption rate is described by an Sshaped curve corresponding to the
dissociation curve of the drug.
• For a simple acid or base, the inflection point of the pH absorption curve
should occur at a pH equal to the pka of the drug. This is rarely observed
experimentally.
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Cont…
• In general pH absorption curves are less step then
expected and are shifted to higher pH values for acids
and to lower pH values for bases.
• The factors that may contribute to the deviations are,
1. Absorption of the ionized form of the drug.
2. Presence of an aqueous unstirred duffusion layer
adjacent to the cell membrane.
3. Difference between luminal pH and pH at the
surface of the cell membrane.
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CONCLUSION
• The pH-partition principle has been tested in large number of IV
and IV studies, and it has been found to be only partly applicable
in real biologic systems. In many cases, the ionized and unionized
forms of a drug partitions are appreciably transported across
lipophilic membrane. But the extension of Ph partition theory to
incorporate the effects of the unstirred layer and microclimate pH
provides a far more satisfactory rationalization of the
experimental data.
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REFERENCE
1. D.M.Brahmankar And S.B.jaiswal,Textbook of
Biopharmaceutics and Pharmacokinetics A
treatise,Sixth edition,Vallabh Prakashan.
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THANK YOU
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