INTRODRUCTION TO

PHARMACOKINETICS
 Introduction
Pharmacokinetics is the subject it deals with the rates of movement of
drug and /or its metabolite (s) in the body and forces acting on the
process
ADME of drugs are the processes in which a drug moves in the body
at various rates
Pharmacokinetics will explain the rates of movement of drugs in the
body with the help of suitable ‘Mathematical Model’
In pharmacokinetics, the concentration of a drug in plasma or any
physiological fluid such as urine, saliva, milk, etc., is determined with
respect to time following its administration
This concentration of drug versus time data is used to study the
dynamics of the drug in the body with the help of mathematical
equations
Mathematical equations are derived based on certain models and set
of assumptions
 Mathematical Model
Mathematical models are a collection of mathematical
quantities, operations and relations together with their
definitions
Qualities of a mathematical model
– Validity
– Generality
– Prediction ability
– Computability
– Consistency of results
Why the data should be fit in a mathematical model?
– To summarize the data observed
– Flexibility
– To calculate the unknown parameters
– To predict valuable information
 Mathematical Model…
– To compare different formulation of a drug
– To compare the drugs with similar pharmacological
action
– To define therapeutic window
– To get answer to various questions pertinent to drug

Drug levels in blood

After extra vascular administration, the drugs reaches the blood
circulation by a process known as absorption

A plot of blood concentration of the drug versus time is utilized

in understanding various important parameters of therapeutics
Blood Level Profile of a Drug following
Oral Administration
Concentration of drug (µg/ml)
Maximum safe level

Therapeutic
C max

Index
Minimum therapeutic level
Onset of action

Termination
of action
Duration of action

T max

Time (Hrs)
 Fraction of Dose absorbed (F)
It is the ratio of the amount of drug ultimately reaching the blood
stream to the total dose administered

The value of F will be unity if the total administered dose

reaches the blood circulation

Many dosage forms often show F values less than unity

because of the following reasons
– Slow release of the drug from the dosage form and
loss of the unabsorbed drug through feces
– Degradation of the drug in the GIT due to chemical or
enzymatic processes
– The drug undergoes the first pass effect
Desired Characteristics of an Ideal Drug
In order to achieve the best therapeutic effect, the drug should
have the below features
– Absorb quickly from the absorption site
– Arrive at the site of action rapidly and in sufficient
quantity
– Remain for the sufficient duration of time
– Be removed from the site of action eventually
– Not get distributed to any other tissue
– Have a large therapeutic index
It is generally difficult to obtain all these characters in a drug
It is very difficult / not practical to know the concentration of the
drug at the tissues in site of action
The basic assumption made to overcome this problem is that,
“there exists a linear relationship between the drug
concentration in blood and the tissues in site of action and the
change in concentration in tissue reflects in blood”
 Pharmacokinetic models
Various mathematical models can be devised to simulate the
rate processes of drug (i.e., ADME)
These mathematical models are useful in the development of
equations to describe drug concentrations in the body as a
function of time
As drug concentrations are dependent on time, the two
variables drug concentration and time are called dependent and
independent variables respectively
In practice, PK parameters are not measured directly but are
determined experimentally from a set of dependent and
independent variables collectively known as data
Generally, the data are analyzed with the simplest
pharmacokinetic model and statistical methods are used to find
out how best the model fits the data
It is very important to realize that PK data should not replace
clinical observations and sound judgment by the clinicians
 Pharmacokinetic models
Pharmacokinetic models are divided into
1. Compartment models
2. Physiological pharmacokinetic models (flow models)
3. Non – Compartmental Pharmacokinetics
4. Non – linear Pharmacokinetics

Compartment models
The human body is assumed to consist of a number of
interconnected compartments
A compartment is defined as a group of tissues which behaves
uniformly with respect to the drug movement
Each tissue may have a different concentration of drug but they all
are in an equilibrium in a way that a change in drug concentration
in these tissues is linear or similar
 Compartment models
Each compartment behaves differently regarding the
concentration time course data
The classification of compartments is based on the degree of
vascularity. i.e., the blood flow to and from the compartment,
like,
1. Highly perfused tissue group: : Consisting of Plasma /
Serum / blood, blood cells, heart, lungs, hepatoportal
system, kidneys, glands and also the brain and spinal cord
2. Poorly perfused tissue group: Consisting of muscle and
skin
3. Fat group: Consisting of adipose tissue including bone
marrow
4. Negligible perfused tissue group: Consisting of bones,
teeth, ligaments, tendons, cartilages and hair
 Compartment models
Mammillary model:
Most common compartment model used in pharmacokinetics
This model consists of one or more peripheral compartments
connected to a central compartment
The central compartment consist of plasma and highly perfused
tissues in which the drug distributes rapidly
The drug introduced into the human body reaches central
compartment and from there it distributes to all other
compartments which are connected to central compartment
Elimination of the drug is assumed to occur from the central
compartment, since the major organs involved in drug
elimination, primarily kidney and liver, are present in the central
compartment
 Compartment models
The drawing of models
– gives a visual representation of the rate processes involved
– how many rate constants are necessary to describe the
process
– Enables to develop differential equations to describe drug
concentration changes in each compartment

Model 1: One – Compartment open model i.v. injection

K
1

Model 2: One – Compartment open model with first order

absorption
Ka K
1
 Compartment models
Model 3: Two – Compartment open model i.v. injection
K12

1 2
K13 K21

Model 4: Two – compartment open model with first order absorption

K12
Ka

1 2
K13 K21

 If the amount of drug absorbed and eliminated per unit time is obtained
by sampling compartment 1, then the amount of the drug contained in the
tissue compartments can be estimated mathematically
 Compartment models
Caternary model:
Compartments joined to one another in a row like the
compartments of a train
K12 K23
1 2 3
K21 K32

In contrast the mammillary model consists of one or more

compartments around a central compartment like satellites

Since most of the functional organs of the body are directly

connected to the plasma, caternary model is not used as often
used as mammillary model
 One compartment open model
Simplest model to describe the movement of the drug in the body

Depicts the body as a single homogeneous unit

The body is open with respect to the drug movement

Useful for drugs which rapidly distribute between plasma and other body
fluids and tissues upon entry into the systemic circulation

Pharmacokinetic models are developed based on some assumptions

(because we are trying to correlate mathematics to physiological events)

The assumptions made should be realistic and practical

 One compartment open model
The following assumptions were made in deriving mathematical
equations for One Compartment Open Model
1. The process of drug absorption from absorption site follows first
order kinetics (mostly drugs absorbed through passive diffusion.
For active transport and facilitated diffusion this is not valid)
2. Drug reaching the systemic circulation is distributed to other
body fluids and tissues and a dynamic equilibrium is achieved
instantaneously
3. Any change that occur in plasma levels of a drug reflect
proportional changes in the tissue levels also (because of dynamic
equilibrium)
4. Elimination of drug from the body through apparent first order
kinetics and its rate constant K is known as apparent first order
rate constant
i.e.,
One compartment open model
the sum of the rate constants of all the processes involved in
elimination of the drug gives an overall apparent first order rate constant K
K = Ke + Kb + Kf1 + Kf2 + ….
Where,
Ke – first order rate constant of renal excretion
Kb – first order rate constant of bile excretion
Kf1 & Kf2 – first order rate constants of metabolism
In order to develop mathematical equations that describe drug
concentration in the body fluid Vs time profile, the following information
should be available
– The dose of drug administered (X0)
– Route of administration (i.v (bolus/infusion) / extra vascular)
– Biological fluid collected for PK (blood/plasma/serum/urine)
– Whether PK study is for single dose / multiple dose
 One compartment open model
Scheme of study of pharmacokinetic equations in one compartmental
open model
Route of administration Biological fluid Drug form
i.v. Bolus Blood / Plasma / Serum Unchanged drug
Urine Unchanged drug
Blood / Plasma / Serum Metabolite(s)
Urine Metabolite(s)
i.v. Infusion Blood / Plasma / Serum Unchanged drug
Urine Unchanged drug
Blood / Plasma / Serum Metabolite(s)
Urine Metabolite(s)
Extra vascular administration Blood / Plasma / Serum Unchanged drug
Urine Unchanged drug