CHAPTER 1

INTRODUC TION
1.1 Biopharmaceutics
The term “Biopharmaceutics” first appeared in a review article, “Bio-pharmaceutics : Absorption
Aspects” edited by Dr. John G. Wagner in the Journal of Pharmaceutical Sciences (Volume 50, pp. 359-
389, 1961). The exact definition given by Wagner in his article is as follows :
“Biopharmaceutics may be defined as the study of the interrelationship of the physicochemical
properties of the drug, the dosage form in which the drug is given and the route of administration on the
rate and extent of systemic drug absorption.”
Thus, biopharmaceutics involves factors that influence are as follows :
(i) Protection of the activity of the drug within the drug product,
(ii) Release of the drug from a drug product,
(iii) Rate of dissolution of the drug at the absorption site, and
(iv) Systemic absorption of the drug.
Fig. 1.1 depicts a general scheme describing the dynamic interrelationship.

The study of biopharmaceutics is based on the fundamental scientific principles and experimental
methodology. These methods must be able to assess the impact of the physical and chemical properties of
the drug, drug stability and large scale production of the drug and drug product on the biological performance
of the drug. Moreover, the biopharmaceutics takes into consideration the requirements of the drug and
dosage form in a physiological environment and the drug’s intended therapeutic use and route of
administration.
Studies in biopharmaceutics use both in-vitro and in-vivo methods. In-vitro methods are procedures
employing test apparatus and equipment without involving laboratory animals or humans. In-vivo methods
are more complex studies involving laboratory animals or human subjects.
Historically, the pharmacologists evaluated the relative systemic drug availability in-vivo after giving
a drug product to an animal or human and then comparing specific pharamacologic, clinical or possible
toxic responses. For example, a drug such as isoproterenol causes an increase in heart rate when given
intravenously but has no observable effect on the heart when given orally at the same dose level. Therefore,
systemic drug availability may differ according to the route of administration.
(1.1)
1.2 Biopharmaceutics and Pharmacokinetics

Aborption of a drug may be defined as the process of movement of drug from its site of administration
to the systemic circulation.
Bioavilability may be defined as the rate and extent (amount) of drug absorption. If there occurs any
alteration in drug’s bioavailability, it is reflected in its pharmacological response. The bioavailability may
differ from one drug product to another containing the same drug. The difference in drug bioavailability
may be manifested by observing the difference in the therapeutic effectiveness of the drug products.
If a change is made in the drug’s bioavailability, it is reflected in its pharmacological effects. The
bioavailability of a drug depends upon the following aspects :
(i) The rate at which the drug is released from its dosage form,
(ii) The extent to which the drug is released from its dosage form,
(iii) The extent of subsequent absorptions from the dissolved (solution) state, and
(iv) The biotransformation occurring during the process of absorption.
The main aim of biopharmaceutical studies is to develop a dosage form which will provide consistent
bioavailability at a desired rate which may not always be rapid one. One can appreciate the importance of
consistent bioavailability provided the drug is having a narrow therapeutic index whereby a slightly higher
bioavailability than expected will give rise to a toxic response and a slightly lower bioavailability will give
rise to a less than minimum effective concentration in the body. Fig. 1.2 depicts narrow therapeutic index.
Thus, the study of biopharmaceutics helps the pharmacist to design drug products rationally to deliver the
active drug at a specific rate and amount into the body to optimize therapeutic effect and to minimize any
adverse effects.

Toxic Concentration
Plasma Concentration

Therapeutic Index
(μg/ml)

Minimum Effective
Concentration

0 2 46 8 10 12
Time in Hours
Fig. 1.2 : Plasma concentration profile showing narrow therapeutic index.
It is possible to do the quantitative determinations in the body fluids such as blood, plasma and urine.
Plasma is usually the most widely used parameter. If a plot is drawn between the plasma concentration in
milliequivalent/ml against time, this provides a lot of informations about the drug in the body and also about
its effectiveness (Fig. 1.3).
From Fig. 1.3, it is evident that
(i) Formulation (a) is considered to be normal but it is almost touching toxic level.
(ii) Formulation (b) is considered to be the best because it is well below the toxic level and above the
minimum effective concentration.
(iii) Formulation (c) is considered to be poor because it is much below the minimum effective concentration.
(iv) Formulation (d) is considered to be dangerous because it is crossing the toxic concentration.
Introduction 1.3

(d)
Drug Plasma Concentration
(c) Toxic
Concentration
(meq/ml)

(b)

(a)
Minimum Effective
Concentration

0 2 4 6 8 10 12
Time (hours)
Fig. 1.3
The difference between the toxic level and minimum effective level is usually termed as therapeutic
window. If the therapeutic window of the drug is wide i.e., the large difference between toxic level and
minimum effective level, the drug is considered to be safe. If the therapeutic window of the drug is narrow,
the margin of safety of the drug is very small. This is true for very few drugs. Some examples are as
follows:
1. Drugs with wide therapeutic window : These have good margins of safety and are therefore safe
drugs. Examples of such drugs are antipyretic analgesics, most of the NSAIDS and antacid drugs.
2. Drugs with narrow therapeutic window : These have small margins of safety. Examples of such
drugs are digoxin, theophylline, isosorbide mononitrate (ISMO), antiarrythemic barbiturates and
barbiturates.
3. Drugs with moderate therapeutic window : These have moderate margin of safety. Examples of
such drugs are cholinergic drugs, antispsmatics, Ca-channel blockers, etc.
The importance of bioavailability is therefore, appreciated when the drug is having narrow therapeutic
window (index) when a slight higher concentration will be able to cross the toxic concentration level and
slightly lower bioavailability will be below the minimum effective concentration.
If two formulations are able to produce the indentical blood level concen-tration and almost identical
drug-concentration-time profiles, they are known as bioequivalent formulations.
Drug disposition may be defined as the distribution and elimination processes when taken together.
It plays a role in the therapeutic activity of a drug.
Drug distribution refers to the movement of drug between one compartment and the other (generally
blood and extravascular tissues). But the site of action is usually situated in the extravascular tissues.
Therefore, the onset, intensity and sometimes duration of action are influenced by the distribution behaviour
of the drug. The intensity (magnitude) and duration of action have been reported to depend mainly upon
the effective concentration and the time period for which this concentration has been maintained at the site
of action which in turn has been found to depend upon the elimination process.
Elimination may be defined as the process which is able to remove the drug from the body as well
as to terminate its action. Elimination takes place by involving the following two processes :
(i) Biotransformation : The metabolism of drug in the body is known as biotransformation. This process
usually inactivates the drug.
(ii) Excretion : The exit of drug/metabolites from the body is known as excertion.
1.4 Biopharmaceutics and Pharmacokinetics

In addition to knowledge of the mechanisms of drug absorption, distribution, metabolism and excretion
(ADME), one should also know the rate at which these processes take place i.e., pharmacokinetics.
Pharmacokinetics may be defined as the study of time course of drug absorption, distribution,
metabolism and excretion (KADME) and their relationship with the therapeutic and toxic effects of the
drug.
Clinical pharmacokinetics may be defined as the application of pharmacokinetic methods in drug
therapy. This is useful in optimising the drug dose to suit individual patient needs and achieving maximum
utility. The study of clinical pharmacokinetics of drugs in disease state requires input from medical and
pharmaceutical research.
It is possible to divide drug administration and therapy into the following four phases or processes :
1. Pharmaceutic process : It deals with the formulation of an effective dosage form of the drug which
is administered by a suitable route.
2. Pharmacokinetic process : It deals with the kinetics of drug absorption, distribution and elimination
(i.e., excretion and metabolism) as elicited by the plasma drug concentration-time profile and its
relation 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. Pharmacodynamic process : It refers to the relationship between the drug concentration at the site
of action (receptor) and pharmacological response, including the biochemical and physiologic effects
that influence the interaction of a drug with receptor. The interaction of a drug molecule with a
receptor causes the initiation of a sequence of molecular events resulting in a pharmacologic or toxic

Drug and Excipients

Pharmaceutics
Formulation

Drug in Dosage Form Drug not Released

Biopharmaceutics

Oral Administration
Adminstration
Parenteral

Drug Release and Drug Decomposed,

Dissolution Metabolized,
Bound or Excreted
Absorption site Absorption
in the GIT
Drug in Systemic
Clinical Pharmacokinetics

Circulation Disposition of Drugs

Pharmacokinetics Distribution Elimination

Extravascular Tissues Metabolism

Tissues at the and
Site of Action Excretion

Pharmaco- Pharmacologic Response

dynamics

Therapeutics Therapeutic/Toxic Effects

Fig. 1.4 : The representation of the processes which are involved in drug therapeutics.
Introduction 1.5

effect. In simple words, pharmacodynamics deals with what the drug does to the body in contrast
to pharmacokinetics which is a study of what the body does to the drug.
4. Therapeutic process : It deals with the translation of pharmacologic effect into clinical benefits.
Fig. 1.4 depicts a schematic representation of the various processes involved in the therapy with a
drug.
In order to attain optimal therapy with a drug, it becomes essential to design the drug product in such
a way that it delivers the active principle at an optimal rate and amount depending upon the patient’s needs.
If one is having knowledge of the factors affecting the bioavailability of drug, then one can design such
an optimum formulation and is able to save many drugs that may be discarded as useless. On the other hand,
it is possible to achieve the rational use to the drug i.e., therapeutic objective, through a better understanding
of pharmacokinetics as well as pharmacodynamic of the drug. This understanding is helpful in designing
a proper dosage regimen i.e., the manner in which the drug is taken. This involves the use of the empirical
approach which requires considerable experimentation to achieve the balance between the desired therapeutic
and undesired toxic effects so as to define an appropriate dosage regimen.
From the knowledge and concepts of biopharmaceutics and pharmaco-kinetics, it becomes possible
to play an integral role in the design and development of new drugs and their dosage form and the
improvement of therapeutic efficacy of the existing drugs.
It is not possible to draw a sharp line of demarcation between biopharmaceutics and pharmacokinetics
because their some areas are overlapping. A schematic representation of the various processes involved in
the therapy with a drug is given in Fig. 1.4.

TEST YOUR KNOWLEDGE

Q. 1.1 What is biopharmaceutics? What is the role of this in pharmacy?
Q. 1.2 What is pharmacokinetics? What is the use of pharmacokinetics?
Q. 1.3 What is bioavailability?
Q. 1.4 What is drug disposition?
Q. 1.5 What is drug distribution?
Q. 1.6 What is elimination of drug?
Q. 1.7 Name and explain the four phases or processes involved in drug administration and therapy.
Q. 1.8 What is clinical pharmacokinetics?
Q. 1.9 What is pharmacodynamics? What is its significance?
Q. 1.10 What is the importance of knowledge of biopharmaceutics and pharmacokinetics.
Q. 1.11 Give a plasma concentration profile showing narrow therapeutic index.
Q. 1.12 What is therapeutic index?
Q. 1.13 What is the goal of biopharmaceutical studies?
Q. 1.14 What is a drug product?