PHARMACOKINETICS

INTRODUCTION

Dr. Rand Shahin

Ref. Dr. Duaa Farah
COURSE OBJECTIVES :
1) Understanding mathematical background for
modeling of the concentration time relationships
for the different routes of p administration.
2) Designing dosing regimens by relating plasma
concentration of drugs to their pharmacological
and toxicological action,

3) Understanding the concept of therapeutic drug
monitoring for drugs with
narrow therapeutic range or high toxicity.
WHAT IS PHARMACOKINETICS?

Pharmacokinetics is the mathematics of the time

course of Absorption, Distribution, Metabolism, and
Excretion (ADME) of drugs in the body.
The biological, physiological, and physicochemical

factors which influence the transfer processes of

drugs in the body also influence the rate and extent
of ADME of those drugs in the body.
In many cases, pharmacological action, as well as

toxicological action, is related to plasma

concentration of drugs.
Consequently, through the study of

pharmacokinetics, the pharmacist will be able to

individualize therapy for the patient.
SEQUENCE OF EVENTS THAT PRECEDE
ELICITATION OF A DRUG'S THERAPEUTIC
EFFECT

First, the drug in its dosage form is taken by the patient by

an oral, intravenous, subcutaneous, transdermal, etc, route
of administration.

Next, the drug is released from the dosage form in a

predictable and characterizable manner.

Then, some fraction of the drug is absorbed from the site of

administration into either the surrounding tissue for local
action or into the body (as with oral dosage forms), or both.

Finally, the drug reaches the site of action.

Scheme demonstrating the dynamic relationship between the drug, the drug
product, and the pharmacologic effect.
SEQUENCE OF EVENTS THAT PRECEDE
ELICITATION OF A DRUG'S THERAPEUTIC
EFFECT

This sequence of events is profoundly affected -in fact,

sometimes organized- by the design of the dosage form, the
drug itself, or both

If the drug concentration at the site of action exceeds the

minimum effective concentration (MEC), a pharmacologic
response results

The actual dosing regimen (dose, dosage form, dosing

interval) was carefully determined in clinical trials to
provide the correct drug concentrations at the site of
action.
SEQUENCE OF EVENTS THAT PRECEDE
ELICITATION OF A DRUG'S THERAPEUTIC
EFFECT
CONCENTRATION TIME PROFILE
 MEC
MTC

Therapeutic range:

Therapeutic index:

Onset of action

Duration of action
PLASMA DRUG CONCENTRATION
TIME CURVE
Therelationshipofthedrugleveltime curve
and
variouspharmacologicparametersforthedrug.
PLASMA DRUG CONCENTRATION
TIME CURVE
Minimumeffectiveconcentration (MEC): reflects the
minimumconcentrationofdrugneededatthereceptorstoproducethe
desiredpharmacologiceffect.

Minimumtoxicconcentration (MTC): represents

thedrugconcentrationneededtojustbarelyproduceatoxic effect.

Theonsettimecorrespondstothetime required for the drug to

reachtheMEC.

Thedurationofdrugactionisthedifferencebetweentheonsettimean
dthetimeforthedrugtodeclineback to the MEC.

Theintensityofthepharmacologiceffectisproportionaltothe number
ofdrugreceptors occupied, which is reflected in the
observationthathigherplasmadrugconcentrationsproduceagreater
pharmacologicresponse, uptoamaximum.
 The aim of biopharmaceutics is to adjust the delivery of
drug to the general circulation in such a manner as to
provide optimal therapeutic activity for the patient.
BIOPHARMACEUTICS
BIOPHARMACEUTICS
PHARMACOKINETICS
ABSORPTION:

Absorption is defined as the net transfer of drug from the

site of absorption into the circulating fluids of the body.

For oral absorption. Two steps are required:

1) crossing the epithelium of the gastrointestinal membrane

either by transcellular or paracellular pathways and
entering the blood stream via capillaries
2) and passing through the hepatoportal system intact into
systemic circulation circulation.

If the drug is metabolized prior to reaching systemic

circulation, it is said to have undergone first-pass
metabolism.
DISTRIBUTION

Drug distribution means the reversible transfer of drug

from one location to another within the body. Once a drug
has entered the vascular system it becomes distributed
throughout the various tissues and body fluids in a pattern
that reflects the physico-chemical nature of the drug and
the ease with which it penetrates different membranes.
ELIMINATION

Metabolism

Metabolism is the bioconversion of drug to another chemical

from or metabolite. mostly by endogenous enzyme systems
involving phase I reactions. Such as oxidation (often by the
cytochrome P-450 system), reduction. hydrolysis, or
dealkylation, or by phase 2 reactions, such as acetylation,
sulfation, or glucuronidation.

Excretion

Excretion is the removal of drug from the body primarily via

urine and occasionally via feces, bile sweat, or exhaled air.
CLINICAL PHARMACOKINETICS

Clinical pharmacokinetics is the application of

pharmacokinetic methods to drug therapy. Clinical
pharmacokinetics involves a multidisciplinary approach to
individually optimized dosing strategies based on the
patient's disease state and patient-specific considerations.

The influence of many diseases on drug disposition is not

adequately studied. Age, gender, genetic, and ethnic
differences can also result in pharmacokinetic differences
that may affect the outcome of drug therapy.

The study of pharmacokinetic differences of drugs in

various population groups is termed population
pharmacokinetics
CLINICAL PHARMACOKINETICS

During the drug development process, large numbers of

patients are tested to determine optimum dosing
regimens, which are then recommended by the
manufacturer to produce the desired pharmacologic
response in the majority of the anticipated patient
population

However, intra- and interindividual variations will

frequently result in either a subtherapeutic (drug
concentration below the MEC) or toxic response (drug
concentrations above the minimum toxic concentration,
MTC), which may then require adjustment to the dosing
regimen
CLINICAL PHARMACOKINETICS
CLINICAL PHARMACOKINETICS
PHARMACODYNAMICS

Pharmacodynamics refers to the relationship between

the drug concentration at the site of action (receptor) and
pharmacologic response, including biochemical and
physiologic effects that influence the interaction of drug
with the 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 response
PHARMACODYNAMICS

Relationship of drug concentrations to drug response.

MEASUREMENT OF DRUG
CONCENTRATIONS
Because drug concentrations are an important element in
determining individual or population pharmacokinetics,
drug concentrations are measured in biologic samples, such
as milk, saliva, plasma, and urine.

Only a few biologic specimens may be obtained safely from

the patient to gain information as to the drug
concentration in the body.
DRUG CONCENTRATIONS IN
BLOOD, PLASMA, OR SERUM

Measurement of drug and metabolite concentrations

(levels) in the blood, serum, or plasma is the most direct
approach to assessing the pharmacokinetics of the drug in
the body.

Whole blood contains cellular elements including red

blood cells, white blood cells, platelets, and various other
proteins, such as albumin and globulins

In general, serum or plasma is most commonly used for

drug measurement.
DRUG CONCENTRATIONS IN
BLOOD, PLASMA, OR SERUM
To obtain serum, whole blood is allowed to clot and the
serum is collected from the supernatant after
centrifugation.

Plasma is obtained from the supernatant of centrifuged

whole blood to which an anticoagulant, such as heparin,
has been added. Therefore, the protein content of serum
and plasma is not the same.

Plasma perfuses all the tissues of the body, including the

cellular elements in the blood. Assuming that a drug in the
plasma is in dynamic equilibrium with the tissues, then
changes in the drug concentration in plasma will
reflect changes in tissue drug concentrations.
DRUG CONCENTRATIONS IN
BLOOD, PLASMA, OR SERUM
DRUG CONCENTRATIONS IN
BLOOD, PLASMA, OR SERUM
DRUG CONCENTRATIONS IN
BLOOD, PLASMA, OR SERUM
Drugs in the plasma are often bound to plasma proteins,
and often plasma proteins are filtered from the plasma
before drug concentrations are measured. This is the
unbound drug concentration.

Alternatively, drug concentration may be measured from

unfiltered plasma this is the total plasma drug
concentration.

When interpreting plasma concentrations, it is important

to understand what type of plasma concentration the data
reflect.
FREQUENTLY ASKED QUESTION

Why are drug concentrations more often measured in plasma

rather than whole blood or serum?

Blood is composed of plasma and red blood cells (RBCs). Serum is

the fluid obtained from blood after it is allowed to clot. Serum and
plasma do not contain identical proteins.
RBCs may be considered a cellular component of the body in

which the drug concentration in the serum or plasma is in

equilibrium, in the same way as with the other tissues in the body.
Whole blood samples are generally harder to process and assay

than serum or plasma samples.

Plasma may be considered a liquid tissue compartment in which

the drug in the plasma fluid equilibrates with drug in the tissues
and cellular components.
PLASMA DRUG CONCENTRATION
TIME CURVE
Theplasmadrugconcentration(level)time curve is
generated by obtaining the drug concentration in plasma
samplestakenat various time intervals after adrug
product is administered.

Theconcentrationofdrugineachplasmasampleisplotte
don rectangular coordinate graph paper against the
corresponding time at which the plasma sample was
removed.
 RATE VS EXTENT
When we talk about the concentration time profile we
are concerned with the ADME processes
Each ADME process has two parameters (Rate and

Extent)
Rate

Extent

As for absorption process, rate is the speed by which

the drug reach the circulation, extent is the amount
of drug that reach the circulation more specifically
the bioavailability of certain drug is 60% this is the
extent
Rate we are concerned if it is zero order or first order
kinetics
 RATE VS EXTENT
As for distribution process , the rate of
distribution process determines if we have one
compartment or two or three compartments
The extent of distribution determines where is
the drug (position of drug) . Example Warferin
99% is bound to plasme protein
This leads us to Volume of distribution which
measures the extent of distribution
 RATE VS EXTENT
As for elimination process
Some drugs are once or twice daily, some drugs
are given once weekly, this is determined by the
rate and extension of elimination process
Volume of distribution
A measure of the tendency of a drug to
move out of the blood plasma to some
other site.
Not a physiological volume
Wont be lower than the blood and plasma
volume
Can be much larger than body volume of
some drugs
It is a mathematical factor that correlates
the amount of drug in the body to its
concentration
Apparent Volume of
Distribution (Vd)
This apparent volume of distribution is not
a physiological volume. It won't be lower
than blood or plasma volume but it can
be much larger than body volume for
some drugs.

It is a mathematical factor relating the

amount of drug in the body and the
concentration of drug in the measured
compartment, usually plasma:
RATES AND ORDERS OF REACTIONS

The rate of a chemical reaction of process is the
velocity with which the reaction occurs. Consider
the following chemical reaction:
B
If the amount of drug A is decreasing with
respect to time (that is, the reaction is going in a
forward direction), then the rate of this reaction
can be expressed as

-
RATES AND ORDERS OF REACTIONS

Since the amount of drug B is increasing with respect
to time, the rate of the reaction can also be expressed
as

Usually only the parent (or pharmacologically active)

drug is measured experimentally. The metabolites of
the drug or the products of the decomposition of the
drug may not be known or may be very difficult to
quantitate. The rate of a reaction is determined
experimentally by measuring the disappearance of
drug A at given time intervals.
RATES OF REACTIONS

The order of a reaction refers to the way in which

the concentration of drugs or reactants influence
the rate of a chemical reaction or process.
Negative charge is due to decrease in
concentration (What is the unit of rate constant?)
CALCULUS

Since pharmacokinetics considers drugs in the

body to be in a dynamic state, calculus is an
important mathematic tool for analyzing drug
movement quantitatively.
Differential equations are used to relate the
concentrations of drugs in various body organs
over time.
Integrated equations are frequently used to
model the cumulative therapeutic or toxic
responses of drugs in the body.
DIFFERENTIAL CALCULUS

Differential calculus is a branch of calculus that

involves finding the rate at which a variable
quantity is changing.
In pharmacokinetics, the amount of drug in the
body is a variable quantity (dependent variable),
and time is considered to be an independent
variable. Thus, we consider the amount of drug to
vary with respect to time.
The derivative dX/dt may be interpreted as a
change in X (or a derivative of X) with respect to
a change in t.
The concentration of drug C in the plasma is declining by 2 g/mL for each
hour of time. The rate of change in the concentration of the drug with respect
to time (ie, the derivative of C) may be expressed as
ZERO ORDER KINETICS

Amount of drug is changing but the rate is constant

What is the expected remained amount after 3 hours?

What is the time needed to get 4 ??g remained?

Half time: time required for drug to drop its

concentration by 50%
In pharmacokinetics, the time required for one-half of the

drug concentration to disappear is known as t.

Can you calculate it in this example?

Half life is dependent on initial amount (no need to

calculate it in zero order kinetics!!!!!

Calculate t for different intervals

Half life depends on the initial amount

 ZERO ORDER RATES
Bus example?????
FIRST ORDER KINETICS
Low concentration of drug!!
Rate is proportional to the amount or
concentration
Rate Amount

Rate = Constant X Amount

Bus example? Rate is dependent on amount

available
FIRST ORDER KINETICS
NORMAL GRAPH PAPER
SEMI LOG PAPER
 Hj
 Unlike a zero-order rate process, the t1/2 for a
first-order rate process is always a constant,
independent of the initial drug concentration or
amount.
A plot between ln c versus t produces a straight
line. A semilogarithmic graph also produces a
straight line between c and t. The units of the
first-order rate constant (k1) are in reciprocal
time.
EXAMPLE
For a drug with k1 = 0.04 h1, find t.
t = 0.693/k1

t = 0.693/0.04 = 17.3 hours

The value 0.04 h1 for the first-order rate

constant indicates that 4% of the drug disappears
every hour.
Calculate the time needed for 70% of the drug to
disappear.
ln c = ln c0 k1t

ln (0.3 c0) = ln c0 k1t

ln (0.3 c0) ln c0 = k1t
NONLINEAR KINETICS
 A solution of a drug was freshly prepared at a
concentration of 300 mg/mL. After 30 days at
25C, the drug concentration in the solution was
75 mg/mL.
a. Assuming first-order kinetics, when will the
drug decline to one-half of the original
concentration?