Pharos University

Faculty of Pharmacy and

Drug Manufacturing,
Department of Pharmaceutics

Yousry M. El-Sayed, Ph.D.

Professor of Pharmaceutics
Spring Semester 2015

Basic Pharmacokinetics
PHR 417

Lectures 1 - 3

Basic Pharmacokinetics
PHR 417
Drug Kinetics Following an Intravenous Bolus Dose
Objectives: At the end of this sequence you will be able to:
1. Explain the assumption of linear one-compartment model.
2. Describe the meaning of an elimination rate constant, and a first
order process.
3. Describe the following terms:
a.
b.
c.
d.

Apparent volume of distribution.

Clearance.
Half-life.
Elimination rate constant.

4. Determine the plasma concentrations, the amount of the drug in the

body, and the apparent volume of distribution when any two of these
values are known.
5. Define; in words and equations; plasma clearance, blood clearance.
6. Explain the statements:
a. The elimination rate constant, or the fraction rate of
elimination, is dependent on the value of the clearance of a
drug and on its apparent volume of distribution.

b. The clearance and the apparent volume of distribution are

independent of the elimination rate constant or the elimination
half-life.
7. Estimate the values of the elimination half-life, elimination rate
constant, apparent volume of distribution and total clearance from
plasma, serum, or blood concentrations following an intravenous
bolus dose.
8. Derive the interrelationship between elimination half-life, elimination
rate constant, apparent volume of distribution and total clearance.
9. Derive and understand the relationship between the administered
dose, total body clearance and area under the plasma concentrationtime curve.
10.Calculate plasma levels at different times, given appropriate data.
Reference:
Chapter 3: Applied Biopharmaceutics and Pharmacokinetics. Edited by:
Leon Shargel, Andrew B.C. Yu ; 5th edition. Publisher: Mc Graw-Hill,
2005

Definition
Pharmacokinetics is the study of drug and/or metabolite kinetics in the
body. It deals with a mathematical description of the rates of drug
movement into, within and exit from the body. It also includes the study of
drug metabolism or biotransformation rates. The body is a very complex
system and a drug undergoes many steps as it is being absorbed,
distributed through the body, and metabolized or excreted (ADME).

Drug Disposition
The drug also interacts with receptors and causes therapeutic and/or toxic
responses. Although the details of drug kinetics are complicated it is
fortunate that we can often approximate drug kinetic processes using
"simple" mathematical models.

One Compartment IV Bolus

Body
Dose

IV

Ab

K
Drug Elimination

Assumptions
We will start the course with a one compartment - linear model. Also, we
will first consider drug kinetics after a rapid intravenous injection, an IV
bolus injection. According to this model we will consider the body to
behave as a single well-mixed container. To use this model mathematically
we need to make a number of assumptions:

1. One compartment
The drug in the blood is in rapid equilibrium with drug in the
extravascular tissues. The drug concentration may not be equal in each
tissue or fluid however they are proportional to the concentration of drug
in the blood at all times.
2. Rapid Mixing
The drug is mixed instantaneously in blood or plasma. The actual time
taken for mixing is usually very short, within few minutes, and in
comparison with normal sampling times it is insignificant. We usually
don't sample fast enough to see drug mixing in the blood.
3. Linear Model
5

For most drugs the elimination follows first order kinetics. First order
kinetics means that the rate of change of drug concentration by any process
is directly proportional to the drug concentration remaining to undertake
that process. Remember first order kinetics is an assumption of a linear
model not a one-compartment model. If we have a linear model, when we
double the dose, the concentration will double at each time point.

Figure of a body before and after a rapid IV bolus injection

The body behaves as a single container or compartment
In order to simplify the mathematics it is often possible to assume that
when a drug is given by rapid intravenous injection, the drug is rapidly
mixed in the body. The Figure above represents the uniformly mixed drug
very shortly after.
Linear Model - First Order Kinetics
First-order kinetics
To illustrate first order kinetics we might consider what would happen if
we were to give a drug by IV bolus injection, collect blood samples at
various times and measure the plasma concentrations of the drug. We
might see a steady decrease in concentration as the drug is eliminated, as
shown in Figure below.

Concentration in the Body (mg/L)

100
80
60
40
20
0

7
9
TIME (Hours)

11

13

Plot of the Concentration versus Time

This can be described mathematically with regard to the amount of drug in
the body as:
Rate of change of the amount of drug in the body:
Change in Ab
dAb

= - K . Ab

dt

Change in time

Proportionality Constant
Called Elimination Rare Constant

Rate of Change in the amount, Ab, with time

Where k is proportionality constant we call a rate constant and Ab is the
amount remaining to be eliminated. Note the use of the symbold to
represent a very small increment in Ab or t. Thus dAb/dt represents the
rate of change of the amount of drug in the body.
Unit of K:
dAb
dt

= - K . Ab

Amount
1
K . Amount
Time-1
Time
Time

The elimination rate constant (K) is also called the fractional rate of
elimination:
7

dAb
dt = K
Ab

(Constant) (First-Order Kinetics)

As the amount of drug in the body decreases so the rate of change

decreases. K remains constant.

First-Order Elimination
Time after Drug
Administration
(hours)

Amount of Drug
in Body (mg)

Amount of Drug
Eliminated Over
Preceding Hour
(mg)

Fraction of Drug
Eliminated Over
Preceding Hour

1000

880

120

0.12

774

106

0.12

681

93

0.12

599

82

0.12

527

72

0.12

464

63

0.12

408

56

0.12

With the first-order elimination process, although the amount of drug

eliminated may change with the amount of drug in the body, the fraction
of a drug in the body eliminated over a given time remains constant. In
practical terms, the fraction or percentage of drug being removed is the
same with either high or low drug concentrations. For example, if 1000 mg
of a drug is administered and the drug follows first-order elimination, we
might observe the patterns in Table above.
8

The actual amount of drug eliminated is different for each fixed time
period, depending on the initial amount in the body, but the fraction
removed is the same, so this elimination is first order. Because the
elimination of this drug (like most drugs) occurs by a first-order process,
the amount of drug eliminated decreases as the concentration in plasma
decreases. The actual fraction of drug eliminated over any given time (in
this case 12%) depends on the drug itself and the individual patients
capacity to eliminate the drug.

dAb

= - K Ab

dt
This is the differential equation for a first-order process and K is the Firstorder rate constant
Differential calculus is involved with the study of rates of processes. The
calculus part comes in when we look at these processes in detail, that is,
during small time intervals.
Rearranging the above equation:

dAb

= - K dt

Ab
Upon integration from t = 0 to t = t

Ln Abt - Ln Ab - K t
Ln Abt Ln Ab - K t

2.303 Log Abt 2.303 Log Ab - K t

Log Abt Log Ab -

K t

Linear First-Order Kinetics

2.303
9

Where Ln is the natural Logarithm

Ln (

Abt
Ab

)= - K t

The antilog:

Abt
Ab

= e- K t

Abt = Ab e- K t
Where Ab0 is the amount of the drug in the body at zero time i.e. time
immediately after injection (DoseIV).

Abt = Dose

IV

e- K t

Linear Scale

Semi-Logarithmic Scal

Abt = Ab e- K t

80
60
40
20
0

7
9
TIME (Hours)

11

13

Amount in the Body (Ab) (mg)

Amount in the Body (Ab) (mg)

100

LogAbt LogAb - K t
2.303
Slope - K
2.303

100
50
20
10
5
2
1

7
8
9
TIME (Hours)

10

11

12

13

14

10

Relationship between Amount and Concentration

Ab Cp

Ab V Cp
V is called Apparent Volume of Distribution (V)

Volume of Distribution

The apparent volume into which a drug distributes in the body at

equilibrium is called the (apparent) volume of distribution.
The Apparent volume of distribution is the factor that relates the plasma
concentration to the amount of drug in the body.
Volume of distribution is useful in estimating plasma concentration when a
known amount of drug is in the body or, conversely, in estimating the dose
required to achieve a desired plasma concentration.

Ab Amount of Drug in the Body

Cp
Plasma Concentration
11

Immediately after the intravenous dose is administered the amount of drug

in the body is the IV dose. Thus:

Dose IV

Cp

Dose IV

Cp

And

Therefore:
Cp =

Dose IV

e- K t

Cp = Cp e- K t
The one compartment model assumption is that there is a rapid
equilibration in drug concentrations throughout the body; however, this
does not mean that the concentration is the same throughout the body.
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 physiochemical nature of the drug and the ease
with which it penetrates different membranes. The ONE COMPARTMENT
model assumes rapid distribution but it does not preclude extensive
distribution into various tissues.

12

The volume of distribution is an important parameter for determining

proper drug dosing regimens. Often referred to as the apparent volume of
distribution, it does not have an exact physiologic significance, but it can
indicate the extent of drug distribution and aid in determination of dosage
required to achieve a desired plasma concentration.
Loading Dose = V X Cpdesired
Where V is the volume of distribution, Cp is the desired plasma level

Drug Concentration in Plasma (mg/L)

Drug Concentration in Plasma (mg/L)

Linear Scale

100

200

Cp = Cp0 e- K t

80
60

monoexponential decline

40
20
0

7
9
TIME (Hours)

11

13

Semi-Logarithmic Scale

100
50

LnCp = LnCp - K t

20
10

Slope - K

5
2
1

7
9
TIME (Hours)

11

13

13

LnCp = LnCp - K t
LogCp = LogCp -

Kt

Slope - K
Slope = -

2.303

K
2.303

Linear plot of ln(Cp) versus time

NOTICE, there are no UNITS for ln(Cp) in the above Figure. There are
units of hour for time (X axis) so the slope has units of time-1 e.g. min-1, hr-1.
Now we can measure the elimination rate constant (k) by determining Cp
versus time and plotting Ln(Cp) versus time.

14

Drug Concentration in Plasma (mg/L)

Semi-Logarithmic Scale

Intercept Cp

200
100

Cp1

Slope

50
20

Ln Cp = Ln Cp - K t

Ln Cp(2) - Ln Cp(1)

Cp2

t2 - t1
Slope - K

10
5
2

t1
0

t2

6
TIME (Hours)

10

12

Determining the Value of K

From the integrated equation:

Ln Cp = Ln Cp - K t
Plotting Ln(Cp) values versus t, time should result in a straight line with a
slope equal to -k, thus k can be calculated as:

K Ln Cp(1) - Ln Cp(2)

Note that Cp1 and Cp2 changed for K to be positive

t2 - t1
Thus with two value for Cp and time data a value for k can be determined.
With more than two Cp - time data points it is possible to plot the data on
semi-log graph paper and draw a 'best-fit' line through the data points.
This plot is shown on the Figure above. Taking points at either end of the
best-fit line can calculate the best answer for k. Using semi-log graph
paper the scale on the y-axis is proportional to the log of the number, not
the number itself.

Note that you can change the sign by calculating the numerator as
Ln (Cp1) Ln (Cp2). Thus k can be calculated using the above equation.

15

Note: It is important to distinguish between the elimination rate and the

elimination rate constant. The rate of elimination (dCp/dt) changes as the
concentration changes, however, for a linear model the rate constant (k) is
constant, it does not change.
Determining the Value of the Apparent Volume of Distribution (V)

Cp = Cp e- K t
We can use the Equation above to calculate the plasma concentration at any
time when we know k and Cp. However, usually we don't know Cp
ahead of time, but we do know the dose. To calculate Cp we need to know
the volume that the drug is distributed into. That is, the apparent volume
of the mixing container, the body. This apparent volume of distribution is
not a physiological volume. It is never lower than blood or plasma volume
but for some drugs it can be much larger than body volume. It is a
mathematical factor relating the amount of drug in the body and the
concentration of drug in the measured compartment, usually plasma.

Cp

Dose IV
V

Cp =

DoseIV

e- K t

V
The usual method of calculating the apparent volume of distribution of the
one compartment model is to extrapolate concentration versus time data
back to the y-axis origin. See below Figure for an example. This gives an
estimate of Cp. When the IV bolus dose is known the apparent volume of
distribution can be calculated from the Equation above.

16

Cp
V

= 40
g/ml

Dose IV
Cp

Dose IV

V
Dose IV
Cp

17

Elimination Half-life (t1/2)

The half-life is the time taken for the plasma concentration to fall to half its
original value. Units for this parameter are units of time such as hour,
minute, or day. Thus if Cp is the concentration at time one (t1), Cp/2 is the
concentration at time one half-life later (t2):

Cp = Cp e- K t

Cp

= Cp e

-Kt
1/2

2
Cp

= Ln Cp - K t
1/2
2
Ln (0.5) = - K t
1/2

Ln

- 0.693 = - K t
1/2

t1/2 = 0.693
K

K = 0.693
t1/2

These Equations can be used to calculate K and t1/2

Semi-log Plot of Cp versus Time illustrating t1/2 Calculation

18

How long it takes to eliminate 90% of the drug from the body? Or how
long it takes for the concentration to fall 90% of the original value?

Cp = Cp e- K t
0.1Cp = Cp e- K t

Note that 90% of the drug eliminated and 10% remaining

Ln 0.1 = - K t

- 2.303 = -

0.693
t
t1/2

t = 3.32 t1/2
Useful values to know:
Time

Remaining fraction of drug in

the body

Fraction lost

1/3 t1/2
1/2 t1/2
1 t1/2
2 t1/2
3.32 t1/2
5 t1/2
6.64 t1/2
10 t1/2

0.8
0.7
0.5
0.25
0.1
3.125 %
0.01
0.001

0.2
0.3
0.5
0.75
0.90
96.875 %
0.99
0.999

Thus over 95 % is lost or eliminated after 5 half-lives. Typically, with

pharmacokinetic processes, this is considered the completion of the process
[Although in theory it takes an infinite time].

19

Total Body Clearance (CL)

Total body clearance or clearance is an important pharmacokinetic
parameter that describes how quickly a drug is eliminated from the body.
It is often defined as the volume of blood or plasma completely cleared of
the drug per time. However, it may be easier to view it as the
proportionality constant relating the rate of elimination and drug
concentration. The rate of elimination of a drug can be described by the
following Equation:

dAb

dAb

Cp

dt

dt

dAb

= CL Cp

= CL Cp

dt

In above Equation the elimination rate, dAb/dt, is related to the

concentration of drug remaining. The proportionality constant for this
relationship is Clearance. The symbol for clearance is CL and the units are
volume per time such as ml/min, L/hr.
Units of Clearance:
Amount
Time

= CL

Amount
Volume

Volume

ml/min or L/hr

Time

20

Dependence of Drug Elimination on Clearance and Distribution

Body
Dose

IV

Ab

Drug Elimination

CL Cp

Rate of Drug Elimination =

dAb

= CL Cp

dt

Ab = V Cp
Note that V is constant

V dcp

= CL Cp

dt
Note that CL is constant

dcp

dt
dcp

CL
Cp
V

= K Cp

dt

21

K=

CL
V

CL = K V
Clearance and Elimination Half-life

t1/2 =

0.693
K

CL = K V
CL =

0.693 V
t1/2

t1/2 =

0.693 V
CL

The previous equation was purposely arranged in the above manner to

stress that, the half-life and elimination rate constant reflects rather than
control the volume of distribution and drug clearance.
One can independently alter the volume of distribution or clearance and
hence change the t1/2 but not vice versa.
In some instance, the volume of distribution and clearance can change to
essentially the same extent, in which case the t1/2 remains unchanged.

22

Example to demonstrate the dependence of the t1/2 on CL and V:

Although the clearance of Quinacrine is very large = 1500 ml/min, it takes
16 days to eliminate 50% of the drug from the body.
Whereas Gentamicin clearance = 120 ml/min, it takes only 1.5 hours to
eliminate 50% of the drug from the body.
The major difference is in Volume of distribution (V):

Quinacrine

CL = 1500 ml/min = 90 L/hr

Quinacrine

t1/2 =

V = 50,000 L

0.693 * 50,000

= 385 hours = 16 days

90

Gentamicin
Gentamicin

t1/2 =

CL = 120 ml/min = 7.2 L/hr

V = 16 L

0.693 * 16

= 1.54 hours

7.2
23

Area under the plasma concentration time curve (AUC)

The area under the plasma (serum, or blood) concentration versus time
curve (AUC) has a number of important uses in toxicology,
biopharmaceutics and pharmacokinetics.

Toxicology: AUC can be used as a measure of drug exposure. It is

derived from drug concentration and time so it gives a measure how much
- how long a drug stays in a body.

Biopharmaceutics: The AUC measured after administration of a drug

product is an important parameter in the comparison of drug products.
Studies can be performed whereby different drug products may be given to
a panel of subject on separate occasions. These bioequivalence or
bioavailability studies can be analyzed by comparing AUC values (This
will be discussed in detail in kinetics of oral administration).

Pharmacokinetics: Drug AUC values can be used to determine other

pharmacokinetic parameters, such as clearance or bioavailability, F.
The area under the plasma concentration versus time curve (AUC) has units
of concentration times time. For example, mg.hr/L or mg.hr.L-1. The area
under the curve is calculated by the Trapezoidal rule.

24

Calculation of AUC using the Trapezoidal Rule

Linear Plot of Cp versus Time showing AUC and AUC segment

If we have a smooth line for concentration versus time or an equation for
Cp versus time from a pharmacokinetic model we could slice the area into
vertical segments. Each segment would be very thin, t and in extreme dt,
in width (much smaller than the segment in Figure above). The total AUC
is calculated by adding these segments together (each Trapezoid). In
calculus this would be the integral. Each very narrow segment has an area
= Cp X dt. Thus the total area (AUC) is given by Equation:

25

AUC (t2 t3) Cp(2 3) dt

t
AUC Cp dt
t 0
Total AUC0

The area under the plasma concentration time curve (AUC) is very useful
for calculating the relative efficiency of different drug products. It can used
to calculate the total body clearance (CL) and the apparent volume of
distribution.

Clearance, Area under the curve and Volume of distribution

So far, clearance has been estimated from the half-life or the elimination
rate constant and volume of distribution:

CL = K V
CL =

0.693 V
t1/2

Clearance can be better estimated in another way:

By rearranging the following equation:

Rate of Drug Elimination =

dAb

CL Cp

= CL Cp

dt
dAb = CL Cp dt

26

Upon integration from t = 0 t =

dAb CL Cp dt
o
o

Ab CL Cp dt

o
Amount lost over all time period (t=0 ) is the dose intravenously
administered.

Dose i.v. CL Cpdt

o

Cpdt AUC 0
o

Dose i.v. CL AUC0

Calculation of drug clearance in this way is independent of the
shape of the plasma concentrations-time profile.
27

CL =

Dose IV
AUC0

Dose IV Cp V

CL = K V
AUC0 = Cp
K

Important terms to remember

Apparent volume of distribution (V):
The apparent volume into which a drug distributes in the body at
equilibrium is called the (apparent) volume of distribution.
The Apparent volume of distribution is the factor that relates the plasma
concentration to the amount of drug in the body.
Volume of distribution is useful in estimating plasma concentration when a
known amount of drug is in the body or, conversely, in estimating the dose
required to achieve a desired plasma concentration.
Clearance (CL):
The factor that relates the amount of the drug eliminated per time
(elimination rate) to plasma concentrations. Or: the volume of plasma the
body has to clear of the drug to account for the total amount removed per
time.
Drug clearance is the factor that relates the plasma concentration to rate of
drug elimination.
Elimination Rate Constant (K):
28

The elimination rate constant is defined as the fraction of the total amount
of drug in the body that is eliminated per unit time.
Elimination Half-life (t1/2):
The elimination half-life is the time taken for the concentration and amount
of drug in the body to fall by one-half.

How to obtain the pharmacokinetic parameters from the plasma

concentrations-time curves?
1. In the table below are the plasma concentration data following an I.V.
bolus dose of a 1 gm of Drug X to a 70-Kg patient:
Time (hr)

1.00

2.00

3.00

4.00

6.00

8.00

10.00 12.00

Concentration (g/ml)

33.6

28.3

23.8

20.0

14.2

10.0

7.1

Prepare linear and semi-logarithmic

concentrations versus times

plots

of

the

5.0

plasma

a. Calculate the volume of distribution.

b. From the slope of the line estimate the elimination half-life and
the elimination rate constant.
c. Calculate the total clearance.
d. Calculate the total area under the plasma concentration-time
curve by the trapezoidal rule.
29

e. Calculate the plasma concentration and the amount of the drug

in the body 24 hours following administration of the drug.

Semi-Logarithmic Plot of the Plasma Concentrations-Time Curve

following I.V. Bolus of 1 gm of Drug X to 70-kg Patient

C
P

= 40
g/ml

30

A. Calculation of the volume of distribution:

The apparent volume of distribution (V) is obtained by dividing the
amount of the drug in the body by the plasma concentration. This
calculation requires that distribution equilibrium was achieved
between the drug in tissues and that in plasma. The amount of drug
in the body is known immediately after an intravenous bolus, it is the
dose administered. However, distribution equilibrium has not yet
been achieved. An estimate is needed of the plasma concentration
that would have resulted when the entire drug spontaneously
distributed into its final volume of distribution. To do this, use is
made of the linear decline during the elimination phase seen in the
semi-logarithmic plot (Figure above).
The decline in the plasma concentrations during the elimination
phase can be described by the linear equation:

Ln Cp = Ln Cp - K t

Cp = Cp e- k t
Cp = Cp at t = 0

as e- 0 = 1

Cp0 is an extrapolated value and is an estimate of the concentration

which when multiplied by the volume term, V, accounts for the dose
administered,

Dose = Cp V
V = Dose
Cp
31

Cp = Cp (extrapolated at t 0)

V = Dose iv
Cp
V=

1000 mg
= 25 L
40 mg/L

B. Estimation of the elimination rate constant and elimination half-life

from the slope of the line:

Cp = Cp e- k t
Ln Cp = Ln Cp - K t

K=

(Ln Cp1 - Ln Cp2)

(t2 - t1)

K=

(Ln 33.6 - Ln 5)

= 0.173 hr - 1

(12 - 1)
t1/2 =

0.693

= 4.0 hrs

K
32

C. Total Clearance:

CL K V
CL 0.173 hr -1 25L 4.33 L/hr
D. Total AUC0 by the Trapezoidal Rule:

AUC t0

AUC t0

AUC

203.3

tn
tn 1

Cpn
k

5
232.20 g/ml.hr
0.173

Another method
AUC0 determination from plasma concentration equations:

Dose i.v. CL AUC 0

Cp V K V AUC0
AUC 0

Cp0 40 g/ml

231.2 g/ml.hr
1
K
0.173 hr

E. Calculate the plasma concentration and the amount of the drug in the
body 24 hours following administration of the drug:

Cp = Cp e- k t

Cp = 40 e- 0.173 24 = 0.63 g/ml

Ab = Cp V

33

Ab = 0.63 g/ml 25 L 15.8 mg

2. Drug: Ampicillin
Clearance: 17 L/hr
Apparent volume of distribution: 25 L
Minimum plasma concentration needed to inhibit Haemophilus
Influenza approximately 0.5 g/ml.
Questions:
A. After a 500 mg i.v. bolus dose of ampicillin, will the plasma
concentration be above the inhibitory concentration of
Haemophilus influenza 6 hours later?

K=

CL

17 L/hr

Cp =

= 0.68 hr - 1

25L

Dose

500 mg

= 20 mg/L = 20 g/ml

25L
Cp = Cp e- k t
Cp = 20 e- 0.68 6 = 0.34 g/ml

34

B. At what time will the concentration drop below 0.5 g/ml?

Cp = Cp e- k t

ln

0.5 = 20 e- 0.68 t *

0.5
= - 0.68 t *
20

- 3.69 = - 0.68 t *
t * = 5.4 hours

C. What dose should be given to achieve a concentration of 0.5

g/ml 6 hours after the dose was given?

Cp = Cp e- k t
0.5 = Cp e- 0.68 6

0.5 = Cp 0.0169

Cp = 29.6 g/ml = 29.6 mg/L

Dose = Cp V = 29.6 mg/L 25L 740 mg

35