ABSORPTION OF DRUG

Nature/ Physiology of cell membranes:-

For systemic drug absorption, drug must cross cellular membranes.
Membrane permeability of drug at absorption site into systemic circulation is
related to molecular structure of drug and physical & biochemical properties of
the cell membranes.

Absorption can also be defined as the process o f movement o f unchanged

-drug from the site o f administration to the site o f measurement i.e. plasma

Trans-cellular absorbtion:
Trans-cellular absorption is the process of drug movement across a cell. Some
polar molecules may not be able to traverse the cell membrane but, instead,
go through gaps or tight junctions between cells, a process known as para-
cellular drug diffusion.
- Membranes are major structures in cells, acting as a boundary between
the cell and the interstitial fluid.
- Cell membranes are semi-permeable partitions that act as selective
barriers to the passage of molecules.
- Cell membranes are generally thin, approximately 70–100 Å in thickness.
Cell membranes are composed primarily of phospholipids in the form of a
bilayer inter-dispersed with carbohydrates and protein groups.

Theories as to the structure of the cell membrane:-

1. Lipid bilayer or unit membrane theory:-
- Proposed by Davson and Danielli (1952),
- Considers the plasma membrane to be composed of two layers of
phospholipid between two surface layers of proteins, with the
hydrophilic “head” groups of phospholipids facing the protein layers
and the hydrophobic “tail” groups aligned in the interior.
- explains the observation that lipid-soluble drugs tend to penetrate cell
membranes more easily than polar molecules.
2. Fluid mosaic model:-
- proposed by Singer and Nicolson (1972)
- explains the transcellular diffusion of polar molecules
- According to this model, the cell membrane consists of globular
proteins embedded in a dynamic fluid, lipid bilayer matrix.
- Two types of pores of about 10 nm and 50–70 nm
- These small pores provide a channel through which water, ions,
dissolve solute more
Mechanism of drug transport:-

The principal mechanisms for transport of drug molecules across the

cell membrane in order of their importance are:

1. Passive diffusion,
2. Pore transport
3. Carrier mediated – a)Facilitated diffusion b)Active transport
4. Ionic or electrochemical diffusion
5. Ion-pair transport
6. Endocytosis

1. Passive diffusion:
Also called nonionic diffusion
it is the major process for absorption o f more than 90% o f the drugs.
The driving force for this process is the concentration or electrochemical
gradient.
It is defined as the difference in the drug concentration on either side o f the
membrane.
OR
Passive diffusion is the process by which molecules spontaneously diffuse
from a region of higher concentration to a region of lower concentration.

If the two sides have the same drug concentration,

forward-moving drug molecules are balanced by molecules moving back,
resulting in no net transfer of drug.
According to Fick’s law of diffusion, drug molecules diffuse from a region of
high drug concentration to a region of low drug concentration. The rate of
transfer is called flux.
𝑑𝑄 𝐷𝐴𝐾
= (𝐶𝐺𝐼 − 𝐶𝑃 ) ---------(1)
𝑑𝑡 ℎ

Where, dQ/dt = rate of diffusion,

D = diffusion coefficient,
A = surface area of membrane,
K = lipid–water partition coefficient of drug in the biologic membrane that
controls drug permeation,
h = membrane thickness, and
𝐶𝐺𝐼 − 𝐶𝑃 = difference between the concentrations of drug in the gastrointestinal
tract and in the plasma.
 A drug is usually given in milligram doses, where as plasma
concentrations are often in the microgram-per-milliliter or nanogramper-
milliliter range.
 If the drug is given orally, then 𝐶𝐺𝐼 >> 𝐶𝑃
 The diffusion coefficient, D, is a constant for each drug and is defined as
the amount of a drug that diffuses across a membrane of a given unit area
per unit time when the concentration gradient is unity.
 The dimensions of D are area per unit time—for example, cm2/sec.
 Because D, A, K, and h are constants under usual conditions for
absorption, a combined constant P or permeability coefficient may be
defined.
𝐷𝐴𝐾
𝑃= ---------(2)
ℎ
From equation 1 and 2, we get,
𝑑𝑄
= 𝑃(𝐶𝐺𝐼 − 𝐶𝑃 ) --------(3)
𝑑𝑡

If the drug is given orally, then CGI >> Cp and a large concentration gradient
is maintained until most of the drug is absorbed.
𝑑𝑄
= 𝑃𝐶𝐺𝐼 ---------(4)
𝑑𝑡
Equation 4 is an expression for a first-order process.
For drugs that act as weak electrolytes, such as weak acids and bases, the
extent of ionization influences the drug’s diffusional permeability.
The ionized species of the drug contains a charge and is more water soluble
than the nonionized species of the drug, which is more lipid soluble.

Characteristics of passive transport:-

- Downhill transport
- Greater the surface area & lesser the thickness of the membrane,
faster the diffusion.
- Equilibrium is attained when the concentration on either side of the
membrane become equal.
- Greater the membrane/ water partition coefficient of drug, faster the
absorption.
- The unionized species are 3-4 times more faster transported
- It is energy independent and non-saturable

2. Carrier mediated transport:-

- Involves a carrier 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 molecules
 - The carrier then returns to its original site to accept a fresh molecule of
solute
Characteristics :-
 The transport process is structure-specific
 Drugs having structure similar to essential nutrients, called as false
nutrients, are absorbed by the same carrier system. For eg.,5-
fluorouracil and 5-bromouracil.
 The transport system is subject to competition between agents having
similar structure.
 The system is capacity limited. capacity-limited process can be
adequately described by mixed order kinetics, also called as
Michaelis-Menten, saturation or non-linear kinetics.
 The process is called mixed order because it is first-order at
subsaturation drug concentrations and apparent zero-order at and
above saturation levels.
 Specialized absorption or carrier-mediated absorption generally occurs
from specific sites of the intestinal tract which are rich in number of
carriers. Such an area in which the carrier system is most dense is
called as absorption window.

- There are two types of carrier mediated transport system:

a) Facilitated diffusion
b) Active transport
(A)Facilitated diffusion:-
 This mechanism involves the driving force is concentration gradient.
 In this system, no expenditure of energy is involved (downhill transport),
therefore the process is not inhibited by metabolic poisons that interfere
with energy production.
 Limited importance in the absorption of drugs.
Eg., 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 vit B2.
 An intrinsic factor (IF), a glycoprotein produced by the gastric parietal cells,
forms a complex with vit B12 which is then transported across the intestinal
membrane by a carrier system.

(B) Active transport:-

 Active transport is a carrier-mediated transmembrane process that plays an
important role in the gastrointestinal absorption and in renal and biliary
secretion of many drugs and metabolite.
 More imp process than facilitated diffusion
 The driving force is against the conc gradient or uphill transport.
 Since the process is uphill, energy is required in the work done by the
barrier.
 As the process requires expenditure of energy, it can be inhibited by
metabolic poisons that interfere with energy production.
 All the binding sites on the carrier may becomes saturated if drug conc is
very high.
 Rate of drug absorption is increase with drug concentration until the carrier
molecule is completely saturated. At higher conc, rate of absorption remain
constant or zero order.
Transporters and various carrier mediated intestinal absorption:-
Various carrier-mediated systems (transporters) are present at the intestinal
brush border and basolateral membrane for the absorption of specific ions and
nutrients essential for the body.
Transporters-- i. influx transporters
ii.efflux transporters

i. Influx transporters:-

(3) Vesicular Transport:-

Vesicular transport is the process of engulfing particles or dissolved materials
by the cell.
It involves engulfing extracellular materials within a segment of the cell
membrane to form a saccule or a vesicle (hence also called as corpuscular or
vesicular transport) which is then pinched off intracellular.
Sometimes ,an endocytotic vesicle is transferred from one compartment to
another. Such phenomenon is called transcytosis.
Endocytosis includes two types of processes
1. Phagocytosis
2. Pinocytosis

Phagocytosis refers to the engulfment of larger particles or macromolecules,

generally by macrophages.
Transcytosis is the process by which various macromolecules are
transported across the interior of a cell. In transcytosis, the vesicle fuses with
the plasma membrane to release the encapsulated material to another side of
the cell.
Eg: administered Sabin polio vaccine and various large proteins.
Pinocytosis is a cellular process that permits the active transport of fluid from
outside the cell through the membrane surrounding the cell into the inside of
the cell.
In pinocytosis, tiny incuppings called caveolae (little caves) in the surface of
the cell close and then pinch off to form pinosomes, little fluid-filled bubbles,
that are free within the cytoplasm of the cell.
Eg: the cellular uptake of macromolecular nutrients like fats and starch, oil
soluble vitamins like A, D, E and K

An example of exocytosis is the transport of a protein such as insulin from

insulin-producing cells of the pancreas into the extracellular space.

(4) Pore (Convective) Transport:-

 also called as convective transport, bulk flow or filtration.
 Very small molecules (such as urea, water, and sugars) are able to cross
cell membranes rapidly, as if the membrane contained channels or pores
 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 molecules occurs through such aqueous channels. Water flux
that promotes such a transport is called as solvent drag.
 A certain type of protein called a transport protein may form an open
channel across the lipid membrane of the cell.

(5) Ion pair transport:

 When ionized drug is linked up with oppositely charged ion, ion pair is
formed in which overall charge of apir neutralizes.
 The neutral drug complex diffuse more easily across membranes.
Eg., Propranolol is a basic drug forms ion pair with oleic acid
Quinine forms ion pair with hexysalicylates.
Complexation of Amphotericin B and DSC (disteroil phosphatidyl
choline)
 Factors influencing GI Absorption of a
Drug from its Dosage Form:-
Factors affecting bioavailability
1. Release of drug from intact formation (dissolution)
-Dissolution rate
-absorption rate
2. Physiological factor
3. Physicochemical factors
4. Dosage form properties

 Physicochemical Factors:
1. Solubility and dissolution
2. Particle size and Surface area
3. Polymorphism and amorphism
4. Pseudopolymorphism (hydrates/solvates)
5. Salt form of the drug
 Factors affecting con of free drug in GI fluid:
1. Complexation
2. Micellar solubalization
3. Adsorption
4. Stability of drug substance in GI fluid
 Factors affecting Permeation
1. Lipid solubility and PKa of drug substance
PH partition Hypothesis and its limitations
2. Dissolution of drug substance and lipid solubility
3. Molecular weight of drug
4. No of hydrogen bond donors and acceptors

Physiological factors affecting oral administration

1. Gastric motility
2. Gastric emptying rate
Factors:-
i. Effect of volume of content
ii. Viscosity
iii. Type of food
a. Fatty acid
b. Triglycerides
c. Carbohydrates
d. Amino acid
 e. Osmotic pressure
f. Effect of acids
g. Effect of alkali
h. Effect of drugs
i. Body position
j. Emotional distress
k. Exercise

3. Effect of food on absorption

I. insoluble complex formation
II. Alteration of GI PH
III. Blood flow
IV. Alteration in metabolism
V. Stability
VI. Gastric emptying
Examples

4. Effect of disease conditions on bioavailability of drug\

Douple peak phenomenon

Particle Size and Effective Surface Area of the Drug

Particle size and surface area of a solid drug are inversely related to each
other. Smaller the drug particle, greater is the surface area.
Larger the surface area, higher is the dissolution rate. Since the surface area
increases with decreasing particle size, a decrease in particle size, which can
be accomplished by micronisation, and will result in higher dissolution rates.
Eg. Poorly water soluble drug GRISEOFULVIN- micronization from 10nm-2.5
m, increases its water solubility
But, micronization of certain water insoluble drugs decreases their
bioavailability. For e.g., Phenacetin, Phenobarbital
As micronization leads to the development of small air pockets due to which
there is less wetting.
Agglomerization takes place due to charge development.
But, when these drugs were subjects to wet milling, there occur increased in
their bioavailability.
During wet milling of phenacetin Tween 80 SLS was added as wetting agent.
Bioavailability of penicllin decreases with size reduction
Examples of drugs whose bioavailability increases after micronization.