Mechanisms for Drug Absorption

1. Dr. Nilesh S. Kulkarni
Associate Professor in Pharmaceutics
PES Modern college of Pharmacy For Ladies Moshi Pune
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2. Absorption
Drug absorption is defined as the process of movement of unchanged
drug from the site of administration to systemic circulation.
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3. ABSORPTION
Drug that have to enter systemic circulation can be administered by
three majority ways
1. Enteral route: includes peroral i.e. gastrointestinal,
sublingual/buccal and rectal routes.
2. Parenteral Route: includes all routes of administration through
or under one or more layers of skin.
3. The Topical Route: includes skin, eyes or other specific membranes.
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4. Gastrointestinal absorption of drugs
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5. Mechanism of Drug Absorption
A. Transcellular/intracellular transport
B. Paracellular/intercellular transport
C. Vesicular transport
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6. A. TRANSCELLULAR/INTRACELLULAR TRANSPORT
The 3 steps involved in transcellular transport of drugs are –
(i) Permeation of GI epithelial cell membrane, a lipoidal barrier – this is the major
obstacle to drug absorption.
(ii) Movement across the intracellular space (cytosol).
(iii) Permeation of the lateral or basolateral membrane- this is of secondary
importance.
Transcellular/intracellular transport
Passive Transport Process Active Transport Process
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7. Passive Transport Process
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
a. Passive diffusion.
b. Pore transport.
c. Ion-pair transport.
d. Facilitated- or mediated-diffusion.
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8. - Most drugs cross biologic membranes by passive diffusion.
- It is defined as the difference in the drug concentration on either
side of the membrane.
- Diffusion occurs when the drug concentration on one side of the
membrane is higher than that on the other side.
- The process is passive because no external energy is expended.
- The driving force for passive diffusion is the difference in drug
concentrations on either side of the cell membrane.
Passive diffusion/ non-ionic diffusion/
concentration or electrochemical gradient.
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9. During passive diffusion, the drug present in 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 Fick’s first law of diffusion,
which 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.
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10. Certain characteristics of passive diffusion can be generalized
1. The drug moves down the concentration gradient indicating downhill transport.
2. The process is energy-independent and non-saturable.
3. The rate of drug transfer is directly proportional to the concentration gradient
between GI fluids and the blood compartment.
4. Greater the area and lesser the thickness of the membrane, faster the diffusion;
thus, more rapid is the rate of drug absorption from the intestine than from the
stomach.
5. The process is rapid over short distances and slower over long distances.
6. Equilibrium is attained when the concentration on either side of the membrane
becomes equal.
7. Drugs which can exist in both ionised and unionised forms approach equilibrium
primarily by the transfer of the unionised species; the rate of transfer of unionised
species is 3 to 4 times the rate for ionised drugs.
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11. 9. The drug diffuses rapidly when the volume of GI fluid is low; conversely,
dilution of GI fluids decreases the drug concentration in these fluids
(CGIT) and lower the concentration gradient (CGIT – C). This
phenomenon is, however, made use of in treating cases of oral overdose
or poisoning.
10.. Greater the membrane/water partition coefficient of drug, faster the
absorption; since the membrane is lipoidal in nature, a lipophilic drug
diffuses at a faster rate by solubilising in the lipid layer of the membrane.
11. The process is dependent, to a lesser extent, on the square root of the
molecular size of the drug – drugs having molecular weights between 100
to 400 Daltons are effectively absorbed passively. The diffusion generally
decreases with increase in the molecular weight of the compound.
However, there are exceptions—for example, cyclosporin A, a peptide of
molecular weight 1200, is absorbed orally much better than any other
peptide.
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12. Ion pair formation
- Strong electrolyte drugs are highly ionized or charged molecules, such as
quaternary nitrogen compounds.
- These drugs penetrate membranes poorly. When linked up with an
oppositely charged ion, an ion pair is formed in which the overall charge of
the pair is neutral. This neutral complex diffuses more easily across the
membrane.
- e.g. the formation of an ion pair for propranolol (basic drug) with oleic acid.
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13. PORE (CONVECTIVE) TRANSPORT:
- A certain type of protein called transport protein may form an open channel across
the lipid membrane of the cell.
- Very small molecules, such as urea, water and sugars are able to rapidly cross the cell
membrane through these pores.
Carrier-Mediated Transport
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14. Carrier Mediated transport
Facilitated Diffusion
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15. Active Transport
Active transport is a more important process than facilitated diffusion in the absorption
of nutrients and drugs
1. The drug is transported from a region of lower to one of higher concentration
i.e. against the concentration gradient (in the case of ions, against an
electrochemical gradient) or uphill transport, without any regard for
equilibrium.
2. The process is faster than passive diffusion.
3. Since the process is uphill, energy is required in the work done by the
carrier.
4. As the process requires expenditure of energy, it can be inhibited by
metabolic poisons that interfere with energy production like fluorides,
cyanide and dinitrophenol and lack of oxygen, etc.
Endogenous substances that are transported actively include sodium,
potassium, calcium, iron, glucose, certain amino acids and vitamins like
niacin, pyridoxin and ascorbic acid.
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16. Drugs having structural similarity to such agents are absorbed actively,
particularly the agents useful in cancer chemotherapy.
Examples include absorption of
5-fluorouracil and 5-bromouracil via the pyrimidine transport system.
absorption of methyldopa and levodopa via an L-amino acid transport system.
absorption of ACE inhibitor enalapril via the small peptide carrier system.
A good example of competitive inhibition of drug absorption via active
transport is the impaired absorption of levodopa when ingested with meals rich
in proteins.
Active transport is also important in renal and biliary excretion of many drugs
and their metabolites and secretion of certain acids out of the CNS.
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17. Active Transport
This transport process requires energy from ATP to move drug molecules from
extracellular to intracellular space.
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18. Active Transport Process
Primary active transport Secondary active transport
1 • Symport
2
• Antiport
1
• Ion Transporter(Organic
Anion Transporter)
2
• ABC (ATP-binding cassett)
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20. PARACELLULAR/INTERCELLULAR TRANSPORT
PARACELLULAR defined as the transport of drugs through the junctions between the
GI epithelial cells. This pathway is of minor importance in drug absorption.
TWO PARACELLULAR TRANSPORT MECHANISMS INVOLVED IN DRUG ABSORPTION
1. Permeation through tight junctions of epithelial cells.
It occurs through openings which are little bigger than
the aqueous pores. Compounds such as insulin and
cardiac glycosides are taken up this mechanism
2. Persorption
Permeation of drug through temporary openings
formed by shedding of two neighbouring epithelial cells
into the lumen.
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21. VESICULAR OR CORPUSCULAR TRANSPORT (ENDOCYTOSIS) TRANSPORT
During pinocytosis or phagocytosis, the cell membrane invaginates to surround the
material, and then engulfs the material into the cell. Subsequently, the cell
membrane containing the material forms a vesicle or vacuole within the cell.
Vesicular transport is the proposed process for the absorption of Vitamin A, D, E, and
K, peptides in new born.
It is the process of engulfing
It is the process of engulfing
particles or dissolved materials
by the cell.
Pinocytosis and phagocytosis
are forms of vesicular transport
that differ by the type of
material ingested.
Pinocytosis: refers to the
engulfment of small molecules
or fluid.
Phagocytosis: refers to the
engulfment of larger particles
or macromolecules.
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