Introduction to

Pharmacokinetics
Pharmaceutics V (PPT 446)
(Lecture 1)

Dr. Rawan Bafail

1
1444 - 2023
How does Pharmaceutics V fit into
my program?

After building a good understanding of all basic

preformulation concepts, such as pharmaceutical
calculations and physical pharmacy, and after
developing practical knowledge and skills in
formulations of medicinal products including
liquid, solid and sterile dosage forms, pharmacists
are required to understand how the human body
deals with drugs once administered
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Topics to be covered
Theoretical
Topic Week No.

Introduction to pharmacokinetics 1

One compartment model – IV bolus 2

Intravenous infusion 3

Multi compartment model – IV bolus 4

Pharmacokinetics of drug absorption 5

Multiple Dosage regimens 6

Introduction to Biopharmaceutics: Plasma concentration time curves and mechanisms of drug

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absorption
Physiological factors effecting drug absorption and effect of food and pathological conditions in drug
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absorption

Non linear Pharmacokinetis 9

Physicochemical factors affecting drug absorption

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Bioavailability and bioequivalence (The use of urinary data in the bioequivalence)

Effect of dosage form on bioavailability 11

Revision 12
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Topics to be covered
Practical
Topic Week No.

Introduction to pharmacokinetics 1

Solving problems on one compartment open model_ IV bolus 2,3

Solving problems on Intravenous infusion 4,5

Solving problems on Multi-compartment open model: IV bolus 6,7

Solving problems on pharmacokinetics of drug absorption 8

Solving problems on multiple dosage regimens 9,10

Solving problems on nonlinear pharmacokinetics 11

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Outcomes & Objectives

Related learning outcome:

ü Outline the different pharmacokinetic models.

Lecture Objectives:

ü Understand the meaning of pharmacokinetics and its process.

ü Recognize the importance of studying pharmacokinetics.

ü Identify the difference pharmacokinetic models following different dosage

form.

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Introduction to Pharmacokinetics
Definitions

Pharmacokinetics: is the quantitative measurement of drug absorption,

distribution, and elimination ( i.e., excretion and metabolism).

It includes the for drug movement into the body, within the body,
and out of the body.

Clinical Pharmacokinetics: is the application of pharmacokinetic methods to drug

therapy.

Clinical pharmacokinetics of drugs is applied in:

ü Various populations groups and is termed population pharmacokinetics.

ü Disease states and requires input from medical and pharmaceutical research.

The pharmacokinetic process of absorption, distribution, metabolism and

elimination is known as ADME.
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Introduction to Pharmacokinetics
Definitions

Absorption: is the process by which a drug proceeds from the site of administration
to the site of measurement (usually blood, plasma or serum).

Distribution: is the process of reversible transfer of drug to and from the site of
measurement (usually blood or plasma).

Any drug that leaves the site of measurement and does not return has undergone
elimination.

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Introduction to Pharmacokinetics

The rate and extent of drug distribution is determined by:

1. How well the tissues and/or organs are perfused with blood.

2. Binding of drug to plasma proteins and tissue components.

3. The permeability of tissue membranes to the drug molecule.

All these factors, in turn, are controlled by the physicochemical properties

and chemical structures (i.e. presence of functional groups) of drugs.

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Introduction to Pharmacokinetics
Definitions

Metabolism: is the process of a conversion of one chemical species to another

chemical species (Fig. 1).

Fig.1: Metabolism of aspirin.

Km (metabolic rate constant).

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Introduction to Pharmacokinetics

Usually, metabolites will possess little or none of the activity of the parent drug.
However, there are exceptions.

Examples of drugs with therapeutically active metabolites are:

Procainamide (antidysrhythmic drug) à Its active metabolite is N-acetyl

procainamide.

Propranolol HCl (β-antagonist) à Its active metabolite is 4-hydroxy-propranolol

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Introduction to Pharmacokinetics
Definitions

Elimination: is the irreversible loss of drug from the site of measurement (blood,
serum, plasma).

Elimination of drugs occur by one or both of:

ü Metabolism.

ü Excretion.

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Introduction to Pharmacokinetics
Definitions

Excretion: is the irreversible loss of a drug in a chemically unchanged form.

An example is shown in (Fig. 2).

Fig.2: Irreversible Loss of Aspirin. 12

Introduction to Pharmacokinetics

1. Organs responsible for drug elimination:

The two principal organs responsible for drug elimination are the kidney and the
liver.

ü The kidney: is the primary site for removal of a drug in a chemically unchanged
form (i.e. excretion) as well as for metabolites.

ü The liver: is the primary organ where drug metabolism occurs.

The lungs occasionally, may be an important route of elimination for substances of

high vapor pressure (i.e. gaseous anesthetics, alcohol, etc.).

Another potential route of drug removal is a mother’s milk. Although not a

significant route for elimination of a drug for the mother, the drug may be consumed
in sufficient quantity to affect the infant.

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Introduction to Pharmacokinetics

Definitions

Disposition:
Once a drug is in the systemic circulation (after intra or extravascular administration),
it is distributed simultaneously to all tissues including the organ responsible for its
elimination.

ü The distinction between elimination and distribution is often difficult. Hence,

disposition is the term used.

ü In other words, disposition is defined as all the processes that occur subsequent to
the absorption of the drug.

ü By definition, the components of the disposition phase are (distribution and

elimination).

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Introduction to Pharmacokinetics

Characterization of drug disposition is an important prerequisite for

determination or modification of dosing regimens (dose and dosing interval)
for individuals and groups of patients.

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Introduction to Pharmacokinetics

The study of pharmacokinetics involves both of:

a. The experimental aspect of pharmacokinetics

It includes the development of:

ü Biologic sampling techniques.

ü Analytical methods for the measurement of drugs and metabolites.

ü Procedures that facilitate data collection and manipulation.

b. The theoretical aspect of pharmacokinetics

It involves the development of: pharmacokinetic models that predict drug

disposition after drug administration.

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Introduction to Pharmacokinetics

2. Measurement of drug concentration:

ü Whole blood contains cellular elements including red blood cells, white blood
cells, platelets, and various other proteins, such as albumin and globulins.

ü To obtain serum, whole blood is allowed to clot and the serum is collected from
the supernatant after centrifugation.

ü Plasma is obtained from the supernatant of centrifuged whole blood to which an

anticoagulant, such as heparin, has been added.

ü Therefore, the protein content of serum and plasma is not the same.

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Introduction to Pharmacokinetics

2. Measurement of drug concentration:

ü 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.

ü Drug concentrations are measured in biologic samples, such as milk, saliva,

plasma, serum and urine.

ü Measurement of drug concentration (levels) in the blood, serum, or plasma is

the most direct approach to assessing the pharmacokinetics of the drug in the
body.

ü Sensitive, accurate, and precise analytical methods should be available for the
direct measurement of drugs in biologic matrices.

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Introduction to Pharmacokinetics

3. Plasma-level time curve :

ü The plasma level-time curve is generated by obtaining the drug concentration in

plasma samples taken at various time intervals after a drug product is
administered.

ü The concentration of drug in each plasma sample is plotted on rectangular

coordinate graph paper against the corresponding time at which the plasma
sample was removed.

ü For extra vascular routes, as the drug reaches the systemic circulation, plasma
drug concentrations will rise up to a maximum.

Usually, absorption of a drug is more rapid than elimination.

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Introduction to Pharmacokinetics
ü As the drug is being absorbed into the systemic circulation, the drug is distributed to
all the tissues in the body and is also simultaneously being eliminated.

ü The relationship of the drug level-time curve and various pharmacologic parameters
for the drug is shown in (Fig. 3).

Fig. 3: Plasma level-time curve after oral administration of a drug. 20

Introduction to Pharmacokinetics

ü MEC (minimum effective concentration) reflects the minimum concentration of drug

needed at the receptors to produce the desired pharmacologic effect. Similarly,

ü MTC (minimum toxic concentration) represents the drug concentration needed to

just barely produce a toxic effect.

ü The onset time corresponds to the time required for the drug to reach the MEC. The
intensity of the pharmacologic effect is proportional to the number of drug receptors
occupied by drug.

ü The duration of drug action is the difference between the onset time and the time
for the drug to decline back to the MEC.

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Introduction to Pharmacokinetics

ü The time of peak plasma level (tmax) is the time of maximum drug concentration in
the plasma and is a rough marker of average rate of drug absorption.

ü The peak plasma level or maximum drug concentration (Cmax) is related to the dose,
the rate constant for absorption, and the elimination constant of the drug.

ü The area under the plasma level time curve (AUC) is related to the amount of drug
absorbed systemically.

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Introduction to Pharmacokinetics

4. Pharmacokinetics model:

A model: is a mathematic description that represents complex physiological

spaces or process.

ü It is used to express quantitative relationships.

ü Such mathematical models can be devised to simulate the rate processes of

drug absorption, distribution, and elimination.

ü Model is used to describe and predict drug concentrations in the body as a

function of time.

ü By fitting the model to the experimental data, the key parameters in a process
are well estimated.

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Introduction to Pharmacokinetics

Pharmacokinetic models are used to:

ü Predict plasma, tissue, and urine drug levels with any dosage regimen.

ü Calculate the optimum dosage regimen for each patient individually.

ü Estimate the possible accumulation of drugs and/or metabolites.

ü Correlate drug concentrations with pharmacologic or toxicological activity.

ü Evaluate differences in the rate or extent of availability between formulations

(bioequivalence).

ü Describe how changes in physiology or disease affect the absorption,

distribution, or elimination of the drug.

ü Explain drug interactions.

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Different models are applied in pharmacokinetics; the most useful
model is the compartment model.
Compartment model:

ü The body is imagined to be composed of mathematically

interconnected compartments.

ü A compartment is not a real physiologic or anatomic region but

is considered as a tissue or group of tissues that have similar
blood flow and drug affinity.

ü Within each compartment, the drug is considered to be

uniformly distributed.

ü Mixing of the drug within a compartment is rapid and

homogeneous.

ü Rate constants are used to represent the overall rate processes

of drug entry into and exit from the compartment.

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Compartment model:

ü ADME processes are ‘‘first order’’ in nature at therapeutic doses

and, therefore, drug transfer in the body is possibly mediated by
passive diffusion.

ü Compartment model, permits us to obtain accurate estimates of

selected fundamental pharmacokinetics parameters such as the
apparent volume of drug distribution, the elimination half life and
the elimination rate constant of a drug.

ü The knowledge of these parameters and the selection of an

appropriate equation constitute the basis for the calculation of
Ø The dosage regimen (dose and dosing interval) that will
provide the desired plasma concentration and duration of
action for an administered drug.

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Compartment model:

ü The model is an open system because drug can be eliminated from

the system.

ü Compartment models are based on linear assumptions using linear

differential equations.

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Mammillary model:

ü It is a compartmental model, consists of one or more compartments

around a central compartment .

ü The mammillary model provides a simple way of grouping all the

tissues into one or more compartments where drugs move to and
from the central or plasma compartment.

ü Drug is both added to and eliminated from a central compartment.

ü The central compartment is assigned to represent plasma and highly

perfused tissues that rapidly equilibrate with drug.

ü When an intravenous dose of drug is given, the drug enters directly

into the central compartment.

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Mammillary model:

ü Elimination of drug occurs from the central compartment because

the organs involved in drug elimination, primarily kidney and liver,
are well-perfused tissues.

ü The mammillary model is the most common compartment model

used in pharmacokinetics (Fig. 4).

ü Depending upon the distribution characteristics of a drug following

its administration, the type of compartment model utilized in
estimation of pharmacokinetics parameters is determined.

ü Generally, the slower the drug distribution in the body, regardless of

the route of administration, the greater the number of
compartments required to characterize the plasma concentration
versus time data, the more complex the equation employed.

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Mammillary model:
The equation required to characterize the plasma concentration versus
time data, however, depends upon the compartment model chosen and
the route of drug administration.

Fig. 4: Various compartment models.

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One-compartment model
ü If the drug is rapidly equilibrates between (the central and the tissue compartment)
following its administration, regardless of the route of administration, then a one-
compartment model is adequately used to describe the plasma concentration
versus time data (Fig.5(A)).

ü The terms rapid and slow distribution refer to the time required to attain
distribution equilibrium for the drug in the body.

ü The attainment of distribution equilibrium means that, the rate of transfer of drug
from blood to various organs and tissues and the rate of transfer of drug from
various tissues and organs back into the blood have become equal.

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Two-compartment model
ü Slow distribution suggests that the distribution equilibrium is attained slowly and at
a finite time (from several minutes to a few hours, depending upon the nature of
the administered drug).

ü Highly perfused systems, such as the liver, the kidney and the blood, may be
pooled together in one compartment i.e. the central compartment (1).

ü Systems that are Not highly perfused, such as bones, cartilage, fatty tissue and
many others, can also be pooled together and placed in another compartment i.e.
the tissue or peripheral compartment (2).

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Two-compartment model
ü In this type of model, the rates of drug transfer from compartment 1 to
compartment 2 and back to compartment 1 will become equal at a time greater
than zero (from several minutes to a few hours) (Fig.5(B)).

ü Although the tissue compartment does not represent a specific tissue, In this
model, the total amount of drug in the body is simply the sum of drug present in
the central compartment plus the drug present in the tissue compartment.

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One Vs. Two compartment model

Fig.5 (A): The distribution phase for Fig.5 (B): Drugs which exhibit a slow equilibration
aminoglycosides is only 15-30 minutes. peripheral tissues Vancomycin is the classic
example, its distribution phase is 1 to 2 hours .

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