On its journey through the body, a drug needs to cross different biological
These barriers can be
- A single layer of cells (e.g. the intestinal epithelium),
- Several layers of cells (e.g. in the skin),
- Or the cell membrane itself (e.g. to reach an intracellular receptor).
A drug can cross a cell layer either by traveling through the cells (transcellular
drug transport) or through gaps between the cells (paracellular drug
A. Transcellular drug transport
•In order to travel through a cell or to reach a target inside a cell, a drug molecule
must be able to tranverse the cell membrane.
•Although cell membranes largely vary in their permeability characteristics
depending on the tissue, the main mechanisms of drugs passing through the cell
membrane are passive diffusion, carrier-mediated processes and vesicular
•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
A.1. Passive Transport Process-
a. Passive diffusion
•Passive diffusion is the process by which molecules spontaneously diffuse
from a region of higher concentration (e.g. outside of the cell) to a region of
lower concentration (e.g. inside the cell), and it is the main mechanism for
passage of drugs through membranes.
•Lipid-soluble drugs penetrate the lipid cell membrane with ease, and can pass
the cell membrane by passive diffusion.
•Also, large molecules, such as proteins and protein-bound drugs, cannot
diffuse through the cell membrane.
•The rate of diffusion depends, apart from the lipid/water partition coefficient of
the drug (P) and the concentration gradient (C-out – C-in), on membrane properties
such as the membrane area (A) and thickness (h), and the diffusion coefficient (D)
of the drug in the membrane, according to Fick's law:
•Many drugs are acidic or basic compounds, which are ionized to a certain degree
in aqueous medium. Their degree of ionization depends on their dissociation
constant (pKa) and the pH of the solution, according to the Henderson-
•Very weak acids with pKa values higher than 7.5, are essentially unionized at
physiological pH values. For these drugs diffusion over the cell membrane is rapid
and independent of pH changes within the body, provided the unionized form of
the drug is lipid soluble.
•For acidic drugs with a pKa value between 3.0 and 7.5, the fraction of unionized
drug varies with the changes in pH encountered in the organism. For these drugs
the pH of the extracellular environment is critical in determining the diffusion
across the cell membrane.
•For acidic drugs with a pKa lower than 2.5, the fraction of unionized drug is low
at any physiological pH, resulting in very slow diffusion across membranes. A
similar analysis can be made for bases.
b. Carrier-mediated processes
• Many cell membranes possess specialized transport mechanisms that regulate
entry and exit of physiologically important molecules and drugs.
• Such transport systems involve a carrier molecule, that is, a trans membrane
protein that binds one or more molecules and releases them on the other side of
• Such systems may operate passively (without any energy source) and along a
concentration gradient; this is called "facilitated diffusion."
• An example is the transport of vitamin B12 across the GI
• At high drug concentrations the carrier sites become saturated, and the rate of
transport does not further increase with concentration. Furthermore,
competitive inhibition of transport can occur if another substrate for this
carrier is present.
Important characteristics of carrier-mediated transports
1. A carrier protein always has an uncharged (non-polar) outer surface which
allows it to be soluble within the lipid of the membrane.
2. The should work efficiently in both direction.
3. Number of carriers are limited, the transport system is subject to competition
between agents having similar structure.
4. Due to limited carriers at higher drug concentration the system becomes
5. Carrier-mediated absorption generally occurs from specific sites of the intestinal
tract which are rich in number of carriers.
c. Ion-Pair Transport
• Mechanism that explains the absorption of drugs like quaternary ammonium
compounds and sulphonic acids, which ionize under all pH conditions, is ion-
• 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.
• For example Propranolol, a basic drug that forms an ion pair with oleic acid,
is absorbed by this mechanism.
d. Pore transport
• It is also known as Convective transport, bulk flow or filtration.
• This mechanism is responsible for transport of molecules into the cell through
the protein channels present in the cell membrane.
i. The driving force is constituted by the hydrostatic pressure or the osmotic
differences across the membrane due to which bulk flow of water along with
small solid molecule occurs through such aqueous channels.
ii. The process is important in the absorption of low molecular weight (less than
100), low molecular size (smaller than the diameter of the pore).
iii. Chain like or linear compounds of molecular weight up to 400 daltons can be
absorbed by filtration.
A.2 Active Transport
• 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.
a. Primary active transport
i. Ion Transporter- Responsible for transporting ions in or out of cells.
e.g.- Proton pump, which is implicated in acidification of
•Two types of ion transporters which play important role in the intestinal absorption of
a.Organic anion transporters: Absorption of drugs such as pravastatin and atorvastatin.
b.Organic cation transporters: Absorption of drugs such as diphenhydramine.
ii. ABC (ATP- binding cassette) transporters:
•Responsible for transporting small foreign molecules (like drugs and toxins) especially
out of the cells i.e. Exsorption and thus called efflux pumps.
•Example of ABC transporter is P-glycoprotein. This later is responsible for pumping
hydrophobic drugs especially anticancer drugs out of cells.
b. Secondary active transport
•In this process there is no direct requirement of ATP.
•The energy required in transporting an ion aids transport of another ion or
molecule (co-transport or coupled transport) either in same direction or in
•This process further divided into-
i.Symport (co-transport)- Movement of both the molecules in same direction.
•E.g. Na+-glucose symporter uses the potential energy of the Na+ concentration
gradient to move glucose against its concentration gradient.
•H+-coupled peptide transporter (PEPT1) which is implied in the intestinal
absorption of peptide-like drug such as beta lactam antibiotics.
ii. Antiport (counter-transport)- Involves movement of molecules in the
•E.g. expulsion of H+ ions using the Na+ gradient in the kidneys.
•Drugs can also cross a cell layer through the small aqueous contact points (cell
junctions) between cells.
•This paracellular drug transport can be initiated by a concentration gradient
over the cell layer (passive diffusion), or by a hydrostatic pressure gradient
across the cell layer (filtration).
•For example, the endothelium of glomerular capillaries in the kidney forms a
leaky barrier, which is very rich in intercellular pores. Therefore, this membrane
is very permeable and permits filtration of water and solutes. On the other hand,
endothelial cells of brain capillaries are sealed together by tight junctions,
practically eliminating the possibility of paracellular drug transport.
B. Paracellular transport/Intercellular transport
There are two paracellular transport mechanisms involved in drug absorption-
i.Permeation through tight junctions of epithelial cells: Basically occurs
through openings which are little bigger than the aqueous pores. Compounds
such as insulin and cardiac glycosides are taken up by this mechanism.
ii.Persorption: Permeation of drug through temporary openings formed by
shedding of two neighboring epithelial cells into the lumen.
C. Vesicular or Corpuscular Transport (Endocytosis)
• During vesicular transport the cell membrane forms a small cavity that
gradually surrounds particles or macromolecules, thereby internalizing them
into the cell in the form of a vesicle or vacuole.
• Vesicular transport is the proposed process for the absorption of orally
administered Sabin polio vaccine and of various large proteins, It is called
endocytosis when moving a macromolecule into a cell.
• Exocytosis when moving a macromolecule out of a cell.
• Transcytosis when moving a macromolecule across a cell.
Vesicular transport of dug can be classed into two categories-
i.Pinocytosis- cell drinking- uptake of fluid solute.
ii.Phagocytosis- cell eating- adsorptive uptake of solid particulates.
1. Brahmankar D.M.,”Biopharmaceutics and Pharmacokinetics- A Treatise”,
Edition, 2009, published by Vallabh Prakashan, pp- 10 to 22.
2. Medicinal Chemistry 1, 2nd
module, Pharmacokinetics and related topics.
3. Images from Google Images.