Pharmacokinetics

1. PHARMACOKINETICS (1203475)
Dr. Mariam Abdel Jalil

3. • Textbook:
Applied biopharmaceutics and pharmacokinetics
Shargel and Yu, 7th edition
• References:
1) Basic pharmacokinetics by Sunil S.
Jambhekar and Philip J. Breen 2nd edition
2) Basic Pharmacokinetics and
Pharmacodynamics_ An Integrated
Textbook and Computer Simulations by Sara
E. Rosenbaum, 2nd edition
3) Essentials of Pharmacokinetics and
Pharmacodynamics, Thomas N. Tozer,
Malcolm Rowland, 2nd edition
• A Useful Web site
http://www.boomer.org/c/p1/

4. Classroom Standards
Excellent attendance is expected
Cell phones silenced please!
All socialization is to be done on your time not
ours! (student chatter: silence can be effective)
Water only in classroom
Raise hand for questions
You are only responsible for your own behavior
Be the best student you can possibly be
Otherwise,… refer back to the university rules,
policies, and procedures

5. Your responsibilities
Always bring your calculator with you
Show effective discipline
Be prepared for class (you should read the
assigned chapters before class and participate in
class and do whatever it takes you to grasp the
material)
You are responsible for all material covered in
the class
or issues
Please communicate any concerns
either in class or at my office hours
Ask questions. Ask lots of questions

6. What is Pharmacokinetics?
From the Greek pharmakon (drug), Kinetics
(movement).
Pharmacokinetics is defined as the science of the
kinetics of drug absorption, distribution, and
elimination (ie, metabolism and excretion).
Thus, the four basic pharmacokinetic process are:
Absorption
Distribution
Metabolism &
Excretion of the drug

8. Why Do We Study Pharmacokinetics?
Pharmacokinetics has many applications those include:
1) Bioavailability measurements and bioequivalence
studies
2) Determining the appropriate dosing regimen for a drug
(the dose, the dosing frequency and the duration of
treatment)
3) Determining the effect of physiological and pathological
conditions such as renal or hepatic dysfunction drug
absorption and disposition and subsequently adjusting
the dosing regimen as necessary

9. Why Do We Study Pharmacokinetics?
4) Estimating possible accumulation of drugs or metabolites
and predicting drug toxicity
5) Evaluating drug interactions
6) Clinical prediction: Using pharmacokinetic parameters to
individualize drug dosing regimen and thus provide the most
effective drug therapy
**** 40% of drugs in the development process fail to be
translated into the market due to pharmacokinetic reasons

10. Review of ADME processes
• Absorption is defined as 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)

11. Review of ADME processes
• The rate and extent of drug distribution is
determined by:
1) How well the tissues and/or organs are perfused
with blood
2) The binding of drug to plasma proteins and
tissue components
3) The permeability of tissue membranes to the
drug molecule.
These factors, in turn, are determined and
controlled by the physicochemical properties and
chemical structures (i.e., presence of functional
groups) of a drug molecule.

12. Review of ADME processes
• Metabolism is the process of a conversion of one
chemical species to another chemical species
• Usually, metabolites will possess little or none of
the activity of the parent drug. However, there are
exceptions (diazepam (Valium) used for
symptomatic relief of tension and anxiety: the
active metabolite is desmethyldiazepam)

13. Review of ADME processes
• Excretion is defined as the irreversible loss of a drug
in a chemically unchanged or unaltered form.
• The two principal organs responsible for drug
elimination (excretion and metabolism) are the
kidney and the liver. The kidney is the primary site for
removal of a drug in a chemically unaltered or
unchanged form (i.e., excretion) as well as for
metabolites.
• 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.).

15. Pharmacodynamics is the study of the
biochemical and physiological effects of drugs
on the body; this includes the mechanisms
of drug action and the relationship
between drug concentration and effect
Pharmacodynamics

16. Pharmacokinetics &Pharmacodynamics
drug in systemic
circulation
drug at the site of action
pharmacologic effect
dose of drug
administered
drug in non-target
tissues
drug metabolized
or excreted
clinical response
efficacy
toxicity
PK
PD
D
A
D
E

17. Pharmacokinetic approaches
• The study of pharmacokinetics involves both
1. experimental and
2. theoretical approaches
***The experimental aspect of pharmacokinetics
involves:
• The development of biologic sampling procedures
• The development of analytical methods for the measurement
of drugs and metabolites
• The development of procedures that facilitate data collection
and manipulation.

18. Pharmacokinetic approaches
 The theoretical aspect involves the development of
pharmacokinetic models that predict drug
disposition after drug administration

19. Measurement of drug/metabolite concentrations
• Drug concentrations are an important element in determining
pharmacokinetic parameters of drug
• Drug concentration provides information such as the amount
of drug retained in, or transported into, that region of the
tissue or fluid, the likely pharmacologic or toxicological
outcome
• Drug concentrations are measured in specific biologic samples,
such as milk, saliva, plasma, and urine
• Sensitive, accurate, and precise analytical methods are used,
especially chromatographic methods to determine the
concentration of various drugs/metabolites

20. Sampling of Biologic Specimens
 Sampling biologic specimens can be conducted
through:
 Invasive methods such as sampling blood, spinal fluid,
synovial fluid, tissue biopsy, or any biologic material that
requires parenteral or surgical intervention in the patient
 Non-invasive methods including urine, feces, saliva,
expired air, or any biologic material that can be obtained
without parenteral or surgical intervention

21. Drug Concentrations in Blood, Plasma,
or Serum
 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

22. Drug Concentrations in Blood, Plasma,
or Serum
 Drug concentrations are more often measured in plasma
 Pharmacologic or toxic effect of a drug is directly related to the
concentration of the drug at the target site (receptors) in the tissue cells,
however, it is difficult to measure the drug concentration at its site of
action
 Since 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 thus
plasma drug level is responsive to the pharmacologic action and
used to monitor drug’s therapeutic behavior

23. Plasma level of the drug
 Monitoring of plasma drug concentrations allows for the
adjustment of the drug dosage in order to individualize and
optimize therapeutic drug regimens (why is optimization
needed?).
 Pharmacokinetic models allow more accurate
interpretation of the relationship between plasma drug levels
and pharmacologic response
 In addition to pharmacokinetic parameters,
pharmacodynamic response is used to monitor therapeutic
effects (give an example).

24. Plasma level-Time curve
• This curve is generated by
obtaining the drug
concentration in plasma
samples taken at various
time intervals after a drug
product is administered.
• 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.

25. Plasma level-Time curve
• MEC (minimum effective
concentration) is the
minimum concentration of the
drug required to produce
pharmacologic effect
• MTC (minimum toxic
concentration) is the drug
concentration needed to just
barely produce a toxic effect
• Therapeutic window is the
range between MEC and MTC

27. Plasma level-Time curve
 The intensity of the pharmacologic effect (magnitude of
effect) is proportional to the number of drug receptors
occupied
 Onset time is the time required for the drug to reach
the MEC
 The duration of drug action is the difference
between the onset time and the time for the drug to
decline back to the MEC

28. Plasma level-Time curve
 Peak plasma concentration
(Cmax): maximum drug
concentration
 Peak time: time to reach
peak plasma level
 AUC: area under the curve

29. Rate processes
• Oftentimes a process such as drug absorption or
drug elimination may be described by the rate by
which the process proceeds. The rate of a process,
in turn may be defined in terms of specifying its
order. In pharmacokinetics, two orders are of
importance, the zero order and the first order.
• Let us introduce the symbol Y as some function
which changes with time (t). This means Y is a
dependent variable and time (t) is an
independent variable.

30. Rate processes
𝑑
𝑡
• The dependent variable (Y) is either mass of drug in the
body (X), mass of drug in the urine (Xu) or the
concentration of drug in plasma or serum (Cp or Cs,
respectively).
• For a very small time interval, there will be a very small
change in the value of Y as follows:
𝑑𝑦
= 𝑌2−𝑌1
𝑡 2−𝑡
1
• where dY/dt is the instantaneous rate of change in function
Y with respect to an infinitesimal time interval (dt).
• In the equation 𝑑𝑦
= KYn
, the numerical value (n) of the
exponent of the
𝑑
s
u
𝑡
bstance (Y) undergoing the change is the
order of the process.

31. Rate processes: zero-order
• The following is the derivation of the equation for a
zero-order elimination process:
𝑑
𝑡
−𝑑𝑦
= K Y0
=K
0 0
• This equation clearly indicates that Y changes at a
constant rate. K0 is a constant (the zero-order rate
constant). This means that the change in Y is
independent of the amount of Y present at a given
time.

32. Rate processes: zero-order
• The integration of the previous equation yields the
following:
• Y=Y0- K0t
• where Y is the amount (or concentration) present at
time t and Y0 is the amount present at time zero. In
the case of an intravenous injection, this amount
would be equal to X0,( i.e. the administered dose.)
1
2
• 𝑡 =
𝑌0
2∗𝐾0

33. Rate processes-First order
• The following is the derivation of the equation for a
first-order elimination process, since the negative
sign indicates that the amount of Y is decreasing
over time. −𝑑𝑦
=KY1
=KY
𝑑𝑡
• the rate at which the mass of Y decreases depends
on the product of the rate of first-order elimination
constant (K) and the mass of the substance
undergoing the change or transfer.
• Upon integration
• 𝑌 = 𝑌0𝑒−𝐾𝑡  lnY=lnY0 - Kt 
0
LogY= Log Y –
𝐾
𝑡
2.303

34. Rate processes-First order
• Upon integration
• 𝑌 = 𝑌0𝑒−𝐾𝑡  lnY=lnY0 - Kt 
0
LogY= Log Y –
𝐾
𝑡
2.303
• 𝑡 1
2
= 0.693
𝐾

36. Example
Time
(min)
Drug A
mg
10 96
20 89
40 73
60 57
90 34
120 10
130 2.5
Time
(min)
Drug B
(mg)
4 70
10 58
20 42
30 31
60 12
90 4.5
120 1.7
Plot the following data both on semi-log graph
and standard rectangular coordinates, and then
answer the following
a.Does the decrease in the
amount of drug A/B appear to be
a zero-order or a first-order
process?
b. What is the rate constant k?
c. What is the half-life t1/2?
d. What is the equation for the
line produced on the graph?

37. 80
70
60
50
40
30
20
10
0
0 50 100 150
Amount
of
B
Time
Drug B
y = -0.7832x + 104.23
R² = 0.9999
0
20
40
60
80
100
120
0 50 100 150
Amount
of
A
Time
Drug A
0
0.5
1
1.5
2
2.5
0 50 100 150
Log
(A)
Time
Drug A
R² = 0.9999
2
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
0 50 100 150
log(B)
Time
Drug B
y = -0.0139x + 1.9044

38. Example
Drug A Drug B
Order of elimination Zero-order First-order
rate constant 0.783 0.032
Half-life 66.6 min 21.6 min
Initial amount 104.2 mg 80.2 mg
Equation of the line A=104.2-0.78t B=79.4*e-.032t

40. Nonlinear kinetics
• Nonlinear pharmacokinetics is also known as
dose-dependent and concentration dependent
pharmacokinetics because the pharmacokinetic
parameters are dependent on the drug
concentration or the drug amount in the body
• At least one of the absorption, distribution, and
elimination processes, which affect the blood
drug concentration—time profile, is saturable and
does not follow first-order kinetics
• The change in drug dose results in
disproportional change in the blood drug
concentration— time profile after single- and
multiple-dose administrations

41. Linear vs nonlinear PK
Linear PK Nonlinear PK
1-Known as dose-independent or
concentration-independent PK.
1-Known as dose-dependent or
concentration-dependent PK.
2-The absorption, distribution
and elimination of the drug
follow first-order kinetics
2-At least one of the PK processes
(absorption, distribution or
elimination) is saturable.
3-The pharmacokinetic
parameters such as the half-life,
total body clearance and volume
of distribution are constant and
do not depend on the drug conc
3-The pharmacokinetic
parameters such as the half-life,
total body clearance and volume
of distribution are conc-
dependant
4-The change in drug dose
results in proportional change in
the drug concentration.
4-The change in drug dose results
in more than proportional or less
than proportional change in the
drug conc.

42. Pharmacokinetic Models
 Drugs are in a dynamic state within the body; they move
between tissues and fluids, bind with plasma or cellular
components, or are metabolized. Those processes (ADME)
are complex and happen simultaneously
 The complexity of these events require the use of
mathematical models and statistics to estimate drug dosing
and to predict the time course of drug efficacy for a
given dose

43. Pharmacokinetic Models
 A Model is a hypothesis using mathematical terms to describe
quantitative relationships.
 One useful model is the compartmental models which allow
the dose and the individual processes of ADME to be combined
in a logical, straightforward manner to create simple models of a
complex physiological system.
 Assumptions are made in pharmacokinetic models to describe a
complex biologic system concerning the movement of drugs
within the body.
 For example, it is assumed that plasma drug concentration
reflects drug concentrations globally within the body

44. Pharmacokinetic Models
A pharmacokinetic function relates an independent variable to a
dependent variable, often through the use of parameters.
For example, a pharmacokinetic model may predict the drug
concentration in the liver 1 hour after an oral administration of a
20-mg dose. The independent variable is the time and the
dependent variable is the drug concentration in the liver.
Based on a set of time-versus-drug concentration data, a model
equation is derived to predict the liver drug concentration with
respect to time (1 hour after an oral administration)

45. Compartmental models
• A compartmental model provides a simple way of
grouping all the tissues into one or more compartments.
The body is represented by a series of compartments that
communicate reversibly with each other.
• Compartmental models are very simple and common.
The mammillary model is the most common
compartment model used in pharmacokinetics.
• Another type is t he catenary model consists of
compartments joined to one another like the
compartments of a train Because the catenary model
does not apply to the way most functional organs in the
body are directly connected to the plasma, it is not
used as often as the mammillary model.

46. Compartmental models
• A compartment is not a real physiologic or anatomic
region, but it is a tissue or group of tissues having similar
blood flow and drug affinity
• Within each compartment the distribution is immediate
and rapidly reversible. The drug is considered to be
uniformly distributed ―kinetic homogeneity‖. This does not
necessarily mean that drug distribution to all tissues of the
central compartment at any given time is the same.
However, it does assume that any change which occurs
in plasma concentration of drug putatively reflects a
change that occurs in all central compartment tissue
concentrations.
• Drug move in and out of compartments
• Compartments are interconnected by first-order rate
constants. Input rate constants may be zero order

47. The model is an open system since drug
is eliminated from the system
The amount of drug in the body is the
sum of drug present in the compartments.
Parameters are kinetically determined
from the data.

49. Compartmental models
• In the one-compartment model, drug is both
eliminated from a central
added to and
compartment. The central compartment is
assigned to represent plasma and highly
perfused tissues that rapidly equilibrate with
drug. When an intravenous dose of drug is given,
the drug enters directly into the central
compartment. Elimination of drug occurs from
the central compartment because the organs
involved in drug elimination, primarily kidney
and liver, are well-perfused tissues.

50. Compartmental models
• In a two-compartment model, drug can move
between the central or plasma compartment to
and from the tissue compartment. Although the
tissue compartment does not represent a specific
tissue, the mass balance accounts for the drug
present in all the tissues. 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.

51. Compartmental models
• The selection of a compartment model depends solely
upon the distribution characteristics of a drug
following its administration.
• The equation required to characterize the plasma
concentration versus time data, however, depends upon
the compartment model chosen and the route of drug
administration.
• 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 is the nature of the equation employed.

52. 58
One compartment Two compartments

53. Following IV
administration
plotting log(C) vs.
time yields a
straight line