Drug absorption

1. By Anjita Khadka
Mechanism of Drug Absorption in
GIT

2. 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.

3. Fig: plots showing significance of rate and extent of absorption in drug therapy

4. Basic structure of functional cell
membrane

5. 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)

6. B. Paracellular/Intercellular Transport:
1. Permeation through tight junctions of epithelial
cells.
2. Persorption
C. Vesicular or corpuscular Transport (Endocytosis):
1. Pinocytosis
2.Phagocytosis

7. 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.

8. • 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 (non-
ionized or non polar):
readily absorbed via cell
membrane itself.
•Depends on lipid
solubility.
•Depends on pka of drug-
pH of medium.

9. •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

10. 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

11. Certain characteristics of passive diffusion contd..
 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)

12. b. Pore transport
 Also called as convective transport, bulk flow or filtration.
Transport of molecules into the cell through the protein channels
present in the cell membrane.
The driving force is constituted by the hydrostatic or the osmotic
pressure differences across the membrane.
Important in the absorption of low molecular weight (<100 dalton),
low molecular size (smaller than the diameter of the pore) and
generally water-soluble drugs through narrow, aqueous filled
channels or pores in the membrane structure.
For example: Urea, water and sugars

13. 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.

14. 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.

16. 2. Active transport Process
 Requires energy in the form of ATP
 Against concentration gradient
 Uphill transport; without any regard for equilibrium.
 Faster than passive diffusion
 Inhibited by metabolic poisons that interfere with energy
production like fluorides, cyanide and dinitrophenol and
lack of oxygen.
 Useful in cancer chemotherapy: 5-fluorouracil,
5-bromouracil
 Important in renal and biliary excretion of many drugs and
metabolites & secretion of certain aciids out of the CNS.

17.  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)

18. 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.

20. 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.

22. 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.

23.  Phagocytosis (cell eating):
 Adsorptive uptake of solid particulates, macromolecules.

24.  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

25. Combined Absorption Mechanisms
 Absorbed by more than just one mechanism. For e.g.
cardiac glycosides (absorbed both passively as well as
by active transport)
 Vitamin B12 (absorbed by passive diffusion, facilitated
diffusion as well as endocytosis)

26. Conclusion
 Passive diffusion: most drugs having high lipophilicity &
MW in the range 100-400 dalton are absorbed.
 Pore transport: water soluble drugs of MW less than 100
dalton are absorbed.
 Ion-pair transport: drugs that ionise at all pH conditions
absorbed after complexing with oppositely charged ions
are absorbed.
 Carrier-mediated transport: structure-specific drugs
with affinity for carriers transported from specific sites are
absorbed.
 Endocytosis: macromolecular nutrients and drugs as solid
particles or oily droplets are absorbed.