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1
Introduction

Drugs, whether obtained from plant, animal or mineral sources or synthesized

chemically, are rarely administered in their pure chemical form. Often, they are
combined with a number of inert substances (excipients/adjuvants) and transformed into
a convenient dosage form that can be administered by a suitable route. Earlier, it was
believed that the therapeutic response to a drug is an attribute of its intrinsic
pharmacological activity. But today, it is very much understood that the dose-response
relationship obtained after drug administration by different routes—for example, oral and
parenteral, are not the same. Variations are also observed when the same drug is
administered as different dosage forms or similar dosage forms produced by different
manufacturers, which in turn depend upon the physicochemical properties of the drug, the
excipients present in the dosage form, the method of formulation and the manner of
administration. A new and separate discipline called biopharmaceutics has therefore
been developed to account for all such factors that influence the therapeutic effectiveness
of a drug.
Biopharmaceutics is defined as the study of factors influencing the rate and amount
of drug that reaches the systemic circulation and the use of this information to optimise
the therapeutic efficacy of the drug products. The process of movement of drug from its
site of administration to the systemic circulation is called as absorption. The
concentration of drug in plasma and hence the onset of action, and the intensity and
duration of response depend upon the bioavailability of drug from its dosage form.
Bioavailability is defined as the rate and extent (amount) of drug absorption. Any
alteration in the drug’s bioavailability is reflected in its pharmacological effects. Other
processes that play a role in the therapeutic activity of a drug are distribution and
elimination. Together, they are known as drug disposition. The movement of drug
between one compartment and the other (generally blood and the extravascular tissues)
is referred to as drug distribution. Since the site of action is usually located in the
extravascular tissues, the onset, intensity and sometimes duration of action depend upon
the distribution behaviour of the drug. The magnitude (intensity) and the duration of
action depend largely upon the effective concentration and the time period for which this
concentration is maintained at the site of action which in turn depend upon the
elimination processes. Elimination is defined as the process that tends to remove the
drug from the body and terminate its action. Elimination occurs by two processes—
biotransformation (metabolism), which usually inactivates the drug, and excretion
which is responsible for the exit of drug/metabolites from the body.
In order to administer drugs optimally, knowledge is needed not only of the
mechanisms of drug absorption, distribution, metabolism and excretion (ADME) but also
of the rate (kinetics) at which they occur i.e. pharmacokinetics. Pharmacokinetics is
defined as the study of time course of drug ADME and their relationship with its
therapeutic and toxic effects of the drug. Simply speaking, pharmacokinetics is the
kinetics of ADME or KADME. The use of pharmacokinetic principles in optimising the
drug dosage to suit individual patient needs and achieving maximum therapeutic utility is
called as clinical pharmacokinetics. Figure 1.1 is a schematic representation of
processes comprising the pharmacokinetics of a drug.

Fig. 1.1. Schematic illustration of pharmacokinetic processes

Drug administration and therapy can now be conveniently divided into four phases or
processes:
1. The Pharmaceutical Phase: It is concerned with –
(a) Physicochemical properties of the drug, and
(b) Design and manufacture of an effective drug product for administration by
a suitable route.
2. The Pharmacokinetic Phase: It is concerned with the ADME of drugs as elicited
by the plasma drug concentration-time profile and its relationship with the dose,
dosage form and frequency and route of administration. In short, it is the sum of all
the processes inflicted by the body on the drug.
3. The Pharmacodynamic Phase: It is concerned with the biochemical and
physiologic effects of the drug and its mechanism of action. It is characterized by
the concentration of drug at the site of action and its relation to the magnitude of
effects observed. Thus, in comparison –
Pharmacokinetics is a study of what the body does to the drug, whereas
Pharmacodynamics is a study of what the drug does to the body.
Pharmacokinetics relates changes in concentration of drug within the body with
time after its administration, whereas
Pharmacodynamics relates response to concentration of drug in the body.
4. The Therapeutic Phase: It is concerned with the translation of pharmacological
effect into clinical benefit.
A schematic representation of the various processes involved in the therapy with a
drug is given in Fig. 1.2.
 Fig. 1.2. Schematic representation of the processes involved in drug therapeutics

To achieve optimal therapy with a drug, the drug product must be designed to
deliver the active principle at an optimal rate and amount, depending upon the patient’s
needs. Knowledge of the factors affecting the bioavailability of drug helps in designing
such an optimum formulation and saves many drugs that may be discarded as useless.
On the other hand, rational use of the drug or the therapeutic objective can only be
achieved through a better understanding of pharmacokinetics (in addition to
pharmacodynamics of the drug), which helps in designing a proper dosage regimen (the
manner in which the drug should be taken). This obviates the use of the empirical
approach where a considerable experimentation is needed to arrive at the balance
between the desired therapeutic and the undesired toxic effects in order to define an
appropriate dosage regimen.

The knowledge and concepts of biopharmaceutics and pharmacokinetics thus

have an integral role in the design and development of new drugs and their dosage forms
and improvement of therapeutic efficacy of existing drugs.
2
Absorption of Drugs
A drug injected intravascularly (intravenously and/or intra-arterially) directly
enters the systemic circulation and exerts its pharmacological effects.
However, majority of drugs are administered extravascularly, generally orally.
If intended to act systemically, such drugs can exert their pharmacological
actions only when they come into blood circulation from their site of
application, and for this, absorption is an important prerequisite step.
Drug absorption is defined as the process of movement of unchanged
drug from the site of administration to systemic circulation. Following
absorption, the effectiveness of a drug can only be assessed by its
concentration at the site of action. However, it is difficult to measure the drug
concentration at such a site. Instead, the concentration can be measured more
accurately in plasma. There always exist a correlation between the plasma
concentration of a drug and the therapeutic response and thus, 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. This definition takes
into account the loss of drug that occurs after oral administration due to
presystemic metabolism or first-pass effect.

Fig. 2.1. Plots showing significance of rate and extent of absorption in drug
therapy.
Not only the magnitude of drug that comes into the systemic circulation but
also the rate at which it is absorbed is important. This is clear from Fig. 2.1.
A drug that is completely but slowly absorbed may fail to show therapeutic
response as the plasma concentration for desired effect is never achieved. On
the contrary, a rapidly absorbed drug attains the therapeutic level easily to
elicit pharmacological effect. Thus, both the rate and the extent of drug
absorption are important. Such an absorption pattern has several advantages:
 1. Lesser susceptibility of the drug for degradation or interaction due
to rapid absorption.
2. Higher blood levels and rapid onset of action.
3. More uniform, greater and reproducible therapeutic response.
Drugs that have to enter the systemic circulation to exert their effect can be
administered by three major routes:
1. The Enteral Route: includes peroral i.e. gastrointestinal,
sublingual/buccal and rectal routes. The GI route is the most common
for administration of majority of drugs.
2. The Parenteral Route: includes all routes of administration through
or under one or more layers of skin. While no absorption is required
when the drug is administered i.v., it is necessary for extravascular
parenteral routes like the subcutaneous and the intramuscular routes.
3. The Topical Route: includes skin, eyes or other specific membranes.
The intranasal, inhalation, intravaginal and transdermal routes may be
considered enteral or topical according to different definitions.
Table 2.1 compares the bioavailability/absorption pattern and advantages
and disadvantages of drugs administered by common routes.
TABLE 2.1.
Bioavailability/absorption of drug from common routes of drug
administration
Route Bioavailability Advantages Disadvantages
Parenteral
Intravenous Complete (100%) Drug is given for Increased chance
(IV) systemic drug immediate or for adverse
absorption. controlled effect. reaction.
May inject large Possible
fluid volumes. anaphylaxis.
Suitable for irritating Requires skill in
drugs insertion of infusion
set.
Tissue damage at
site of injection
(infiltration,
necrosis, or sterile
abscess).
Intramuscular Rapid absorption Easier to inject than Irritating drugs
injection (IM) from aqueous intravenous may be very
solutions. injection. painful.
Slow absorption Larger volumes Variable rates of
from non-aqueous may be used absorption
(oily) solutions. compared to depending upon
subcutaneous muscle group
solution. injected and blood
flow.
Subcutaneous Rapid absorption Generally, used for Rate of drug
injection (SC) from aqueous vaccines and drugs absorption depends
solution. not absorbed orally upon blood flow
Slow absorption e.g. insulin. and injection
from depot volume.
formulations.
Enteral Routes
Buccal or Rapid absorption of No presystemic Some drug may be
sublingual lipid-soluble drugs. metabolism. swallowed. Not for
(SL) most drugs or
drugs with high
doses.
Oral (PO) Absorption may Safest and easiest Some drugs are
vary. Generally route of drug unstable in GIT, or
slower absorption administration. undergo
rate compared to IV Suitable for both presystemic
bolus or IM injection. immediate-release metabolism or
and modified- show erratic
release drug absorption.
products.
Rectal (PR) Absorption may Useful when patient Absorption may be
vary from cannot swallow erratic. Suppository
suppository. medication. may migrate to
More reliable Used for local and different position.
absorption from systemic effects. Some patient
enema (solution). discomfort.
Other Routes
Transdermal Slow absorption, Transdermal Some irritation by
rate may vary. delivery system patch or drug.
Increased (patch) is easy to Permeability of
absorption with use and withdraw. skin variable with
occlusive dressings. Continuous release condition, anatomic
for a specified site, age, and
period. gender.
Used for lipid- Type of cream or
soluble drugs with ointment base
low dose and low affects drug release
MW. and absorption.
Low presystemic
metabolism.
Inhalation Rapid absorption. May be used for Particle size of
Total dose local or systemic drug determines
absorbed is effects. anatomic
variable. placement in
respiratory tract.
May stimulate
cough reflex.
Some drug may be
swallowed.

GASTROINTESTINAL ABSORPTION OF DRUGS

The oral route of drug administration is the most common for systemically
acting drugs and therefore, more emphasis will be given to gastrointestinal
(GI) absorption of drugs. Moreover, it covers all the aspects of variability
observed in drug absorption. Before proceeding to discuss absorption aspects,
a brief description of cell membrane structure and physiology is necessary.
Cell Membrane: Structure and Physiology
For a drug to be absorbed and distributed into organs and tissues and
eliminated from the body, it must pass through one or more biological
membranes/barriers at various locations. Such a movement of drug across the
membrane is called as drug transport.
The basic structure of cell membrane is shown in Fig. 2.2.

Fig. 2.2. Basic structure of functional cell membrane

The cellular membrane consists of a double layer of amphiphilic
phospholipid molecules arranged in such a fashion that their hydrocarbon
chains are oriented inwards to form the hydrophobic or lipophilic phase and
their polar heads oriented to form the outer and inner hydrophilic boundaries
of the cellular membrane that face the surrounding aqueous environment.
Globular protein molecules are associated on either side of these hydrophilic
boundaries and also interspersed within the membrane structure. In short, the
membrane is a mayonnaise sandwich where a bimolecular layer of lipids is
contained between two parallel monomolecular layers of proteins. The
hydrophobic core of the membrane is responsible for the relative
impermeability of polar molecules. Aqueous filled pores or perforations of 4
to 10 Å in diameter are also present in the membrane structure through which
inorganic ions and small organic water-soluble molecules like urea can pass.
In general, the biomembrane acts like a semipermeable barrier permitting
rapid and limited passage of some compounds while restricting that of others.
The GI lining constituting the absorption barrier allows most nutrients like
glucose, amino acids, fatty acids, vitamins, etc. to pass rapidly through it into
the systemic circulation but prevents the entry of certain toxins and
medicaments. Thus, for a drug to get absorbed after oral administration, it
must first pass through this biological barrier.

MECHANISMS OF DRUG ABSORPTION

The three broad categories of drug transport mechanisms involved in
absorption are –
A. Transcellular/intracellular transport
 B. Paracellular/intercellular transport
C. Vesicular transport

A. Transcellular/Intracellular Transport – is defined as the passage of

drugs across the GI epithelium. It is the most common pathway for drug
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.
The various transcellular transport processes involved in drug absorption are –
1. Passive Transport Processes – 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.

2. Active Transport Processes – This transport process requires

energy from ATP to move drug molecules from extracellular to
intracellular milieu. These are of two types –
a. Primary active transport.
b. Secondary active transport – this process is further
subdivided into two –
i. Symport (co-transport).
ii. Antiport (counter-transport).

B. Paracellular/Intercellular Transport – is defined as the transport of

drugs through the junctions between the GI epithelial cells. This pathway
is of minor importance in drug absorption. The two paracellular transport
mechanisms involved in drug absorption are –
1. Permeation through tight junctions of epithelial cells – this
process basically 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 – is permeation of drug through temporary
openings formed by shedding of two neighbouring epithelial
cells into the lumen.
 Paracellular transport differs from pore transport in that the former
involves transfer of drug across epithelium and through the cellular junctions
whereas in the case of latter, the molecules are transferred from outside of the
epithelial cell into the cell through pores present in the cell membrane.

C. Vesicular or Corpuscular Transport (Endocytosis) – Like active

transport, these are also energy dependent processes but involve transport
of substances within vesicles into a cell. Since the mechanism involves
transport across the cell membrane, the process can also be classified as
transcellular. Vesicular transport of drugs can be classed into two
categories –
1. Pinocytosis.
2. Phagocytosis.

Figure 2.3. compares transcellular, paracellular and vesicular transport

mechanisms.

Fig. 2.3. Illustrative comparison of transcellular, paracellular and vesicular

transport.
Passive Diffusion
Also called non-ionic diffusion, it is the major process for absorption of more
than 90% of 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 of the membrane. Drug movement is a result of
the kinetic energy of molecules. Since no energy source is required, the
process is called as passive diffusion. 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. It can be mathematically expressed by the following equation:
dQ DAK m/w
CGIT - C (2.1)
dt h
where,
dQ/dt = rate of drug diffusion (amount/time). It also represents the rate of
appearance of drug in blood
D = diffusion coefficient of the drug through the membrane
(area/time)
A = surface area of the absorbing membrane for drug diffusion (area)
Km/w = partition coefficient of the drug between the lipoidal membrane
and the aqueous GI fluids (no units)
(CGIT – C) = difference in the concentration of drug in the GI fluids
and the plasma, called as the concentration gradient
(amount/volume)
h = thickness of the membrane (length)
Based on the above equation, 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.
8. 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.
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. 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.
Initially, when the drug is ingested, CGIT >> C and a large concentration
gradient exists thereby acting as the driving force for absorption. As
equilibrium approaches, the drug diffusion should stop and consequently a
large fraction of drug may remain unabsorbed. But this is not the case; once
the passively absorbed drug enters blood, it is rapidly swept away and
distributed into a much larger volume of body fluids and hence, the
concentration of drug at the absorption site, CGIT, is maintained greater than
the concentration of drug in plasma. Such a condition is called as sink
condition for drug absorption.
Since under usual conditions of absorption, D, A, Km/w and h are
constants, the term DAKm/w/h can be replaced by a combined constant P
called as permeability coefficient. Permeability refers to the ease with which
a drug can penetrate or diffuse through a membrane. Moreover, due to sink
conditions, the concentration of drug in plasma C is very small in comparison
to CGIT. As a result, equation 2.1. may be simplified to:
dQ (2.2)
PCGIT
dt
Equation 2.2 is an expression for a first-order process. Thus, passive
diffusion follows first-order kinetics. Since a large concentration gradient
always exists at the absorption site for passive diffusion, the rate of drug
absorption is usually more rapid than the rate of elimination. Besides, dilution
and distribution of the absorbed drug into a large pool of body fluids and its
subsequent binding to various tissues are other reasons for elimination being
slower than absorption.
Figure 2.4 illustrates the relative permeability of different molecules to
lipid bilayer.
 Fig. 2.4. Relative passive diffusion rate of different types of molecules
Pore Transport
It is also called 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. Following are the
characteristics of pore transport –
1. 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.
2. The process is important in the absorption of low molecular weight (less
than 100), 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.
3. Chain-like or linear compounds of molecular weight up to 400 Daltons
can be absorbed by filtration.
Drug permeation through water-filled channels is of particular importance
in renal excretion, removal of drug from the cerebrospinal fluid and entry of
drugs into the liver.
Ion-Pair Transport
Yet another mechanism that explains the absorption of drugs like quaternary
ammonium compounds and sulphonic acids, which ionise under all pH
conditions, is ion-pair transport. 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. Such a phenomenon is called as ion-pair transport
(Fig. 2.5). Propranolol, a basic drug that forms an ion pair with oleic acid, is
absorbed by this mechanism.
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