One Compartment

Open Model
IV bolus
Dr Mohammad Issa
1

One compartment

More than one compartment

One compartment open model

The one-compartment open model offers the simplest

way to describe the process of drug distribution and
elimination in the body.

This model assumes that the drug can enter or leave the
body (ie, the model is "open"), and the body acts like a
single, uniform compartment.

The simplest route of drug administration from a

modeling perspective is a rapid intravenous injection (IV
bolus).

One compartment open model

The simplest kinetic model that describes drug

disposition in the body is to consider that the
drug is injected all at once into a box, or
compartment, and that the drug distributes
instantaneously and homogenously throughout
the compartment.

Drug elimination also occurs from the

compartment immediately after injection.
5

One compartment:

Properties of a Pharmacokinetic
Compartment
1.

Kinetic homogeneity. A compartment contains tissues that can

be grouped according to similar kinetic properties to the drug
allowing for rapid distribution between tissues

2.

Although tissues within a compartment are kinetically

homogeneous, drug concentrations within a compartment may
have different concentrations of drug depending on the
partitioning and binding properties of the drug.

3.

Within each compartment, distribution is immediate and rapidly

reversible.

4.

Compartments are interconnected by first-order rate constants.

Input rate constants may be zero order
7

One compartment:
IV bolus
administration
(dose = X0)

Drug amount in the

Body (X)

Elimination process
Elimination rate
constant (K)

Based on the assumption of first order elimination process:

elimination rate K X
8

One compartment open model

Drug Conc (C)

D K t
C
e
Vd

Time

C= concentration
D= dose
Vd: Volume of distributio
K: elimination rate
constant
t: time
9

How to distinguish one comp?

log (C)

Plotting log(C) vs. time yields a

straight line

Time
10

Fundamental parameters in one

compartment
Apparent Volume of Distribution (Vd)
Elimination rate constant (K)
Elimination half life (t1/2)

Clearance (Cl)

11

Apparent Volume of Distribution

(Vd)
100 mg

C= 10 mg/L

C= 1 mg/L

Vd= 10 L

Vd= 100 L

12

Apparent Volume of Distribution

(Vd)

In general, drug equilibrates rapidly in the body. When plasma or

any other biologic compartment is sampled and analyzed for
drug content, the results are usually reported in units of
concentration instead of amount

Each individual tissue in the body may contain a different

concentration of drug due to differences in drug affinity for that
tissue. Therefore, the amount of drug in a given location can be
related to its concentration by a proportionality constant that
reflects the volume of fluid the drug is dissolved in

The volume of distribution represents a volume that must be

considered in estimating the amount of drug in the body from the
concentration of drug found in the sampling compartment
13

The real Volume of Distribution has physiological

meaning and is related to body water
Total body water 42 L
Plasma
Interstitial
fluid

Intracellular
fluid

Plasma volume 4 L
Interstitial fluid volume 10 L

Intracellular fluid volume 28 L

14

Apparent Volume of Distribution

Drugs which binds selectively to plasma proteins, e.g.

Warfarin have apparent volume of distribution smaller
than their real volume of distribution

Drugs which binds selectively to extravascular tissues,

e.g. Chloroquines have apparent volume of distribution
larger than their real volume of distribution. The Vd of
such drugs is always greater than 42 L (Total body
water)

15

Apparent Volume of Distribution

Lipid solubility of drug
Degree of plasma protein binding
Affinity for different tissue proteins
Fat : lean body mass
Disease like Congestive Heart Failure
(CHF), uremia, cirrhosis

16

Apparent Volume of Distribution

In general, drug equilibrates rapidly in the body. When plasma or

any other biologic compartment is sampled and analyzed for
drug content, the results are usually reported in units of
concentration instead of amount

Each individual tissue in the body may contain a different

concentration of drug due to differences in drug affinity for that
tissue. Therefore, the amount of drug in a given location can be
related to its concentration by a proportionality constant that
reflects the volume of fluid the drug is dissolved in

The volume of distribution represents a volume that must be

considered in estimating the amount of drug in the body from the
concentration of drug found in the sampling compartment
17

Apparent Volume of Distribution:

Mathematics

In order to determine the apparent volume of distribution

of a drug, it is necessary to have plasma/serum
concentration versus time data

X0
dose
Vd

initial conc. C 0

18

Apparent volume of distribution

estimation
1.

Plot log(C) vs. time

2.

Plot the best-fit line

3.

Extrapolate to the Y-axis intercept (to estimate

initial concentration, C0)

4.

Estimate Vd:

X0
dose
Vd

initial conc. C 0
19

Log (Conc)

1- Plot log(C) vs. time

Time
20

Log (Conc)

2- Plot the best-fit line

Time
21

Log (Conc)

3-Extrapolate to the Y-axis intercept

(to estimate C0)

C0

Time
22

Log (Conc)

4-Estimate Vd
X0
dose
Vd

initial conc. C 0
Log(C0)

Time
23

The Extent of Distribution and Vd in

a 70 kg Normal Man
Vd, L

% Body
Weight

Extent of Distribution

Only in plasma

5-20

7-28

In extracellular fluids

20-40

28-56

In total body fluids.

>56

In deep tissues; bound to

peripheral tissues

>40

24

Elimination rate constant (K)

Elimination rate constant represents the fraction

of drug removed per unit of time

K has a unit of reciprocal of time (e.g. minute -1,

hour-1, and day-1)

With first-order elimination, the rate of

elimination is directly proportional to the serum
drug concentration
25

Elimination rate constant estimation

1.

Plot log(C) vs. time

2.

Plot the best-fit line

3.

Calculate the slope using two points on the

best-fit line
Estimate K: K Slope 2.303

4.

26

Log (Conc)

1- Plot log(C) vs. time

Time
27

Log (Conc)

2- Plot the best-fit line

Time
28

Log (Conc)

3- Calculate the slope using two

points on the best-fit lin
log(C1 ) log(C2 )
Slope
t1 t 2

(Log(C1), t1)
(Log(C2), t2)

Time
29

4- Estimate K

Log (Conc)

K Slope 2.303

Time
30

Elimination half life (t1/2)

The elimination half life is sometimes

called biological half-life of a drug

The elimination half life is defined as the

time (h, min, day, etc.) at which the mass
(or amount) of unchanged drug becomes
half (or 50%) of the initial mass of drug
31

Elimination half life (t1/2) estimation

Two methods:
From

the value of K:

t1/ 2
Directly

0.693

from Conc vs. time plot

Select a concentration on the best fit line (C1)

Look for the time that is needed to get to 50% of
C1 half-life

32

Clearance (Cl)

Clearance is a measure of the removal of drug

from the body

Plasma drug concentrations are affected by the

rate at which drug is administered, the volume in
which it distributes, and its clearance

A drugs clearance and the volume of distribution

determine its half life
33

Clearance (Cl)

Clearance (expressed as volume/time) describes the removal of

drug from a volume of plasma in a given unit of time (drug loss
from the body)

Clearance does not indicate the amount of drug being removed. It

indicates the volume of plasma (or blood) from which the drug is
completely removed, or cleared, in a given time period.

Figures in the following two slides represent two ways of thinking

about drug clearance:

In the first Figure, the amount of drug (the number of dots) decreases
but fills the same volume, resulting in a lower concentration
Another way of viewing the same decrease would be to calculate the
volume that would be drug-free if the concentration were held constant
as resented in the second Figure

34

Clearance (Cl)

the amount of drug (the number of

dots) decreases but fills the same
volume, resulting in a lower
concentration
35

Clearance (Cl)

36

Clearance (Cl)

The most general definition of clearance is that it is a

proportionality constant describing the relationship
between a substances rate of elimination (amount per
unit time) at a given time and its corresponding
concentration in an appropriate fluid at that time.

Clearance can also be defined as the hypothetical

volume of blood (plasma or serum) or other biological
fluids from which the drug is totally and irreversibly
removed per unit time.

37

Clearance (Cl) estimation

For ALL LINEAR pharmacokinetics (including

one compartment) , clearance is calculated
using:

dose
Cl
AUC

where AUC is the area under the concentration

curve (it will be discussed later)
38

Clearance (Cl) estimation

For One compartment pharmacokinetics ,

clearance is calculated using:

Cl K Vd

39

Clearance (Cl)

Drugs can be cleared from the body by

different pathways, or organs, including
hepatic biotransformation and renal and
biliary excretion. Total body clearance of a
drug is the sum of all the clearances by
various mechanisms.

Cl t Cl r Cl h Cl other

(Cl t , Cl r and Cl h total, renal, and hepatic Cl)

40

Elimination rate

The elimination rate at any time can be

calculated using:
Elimination

rate = K*X(t)

OR
Elimination rate = Cl*C(t)

where

X(t) is the amount of drug in the body at time t,

C(t) is the concntration of drug at time t
41

Area Under the Conc. Time Curve

(AUC) calculation

Two methods:
Model

dependent: can be used only for one

compartment IV bolus
Model independent: Can be used for any drug
with any route of administration

42

AUC calculation: Model dependent

With one compartment model, first-order

elimination, and intravenous drug
administration, the AUC can be calculated
using:

Dose C0
AUC

K Vd K

43

AUC calculation: Model

independent

44

AUC calculation: Model

independent
1- Divide the area into different parts
based on the observed concentration
points (parts 1-5)

1
2
3

5
45

AUC calculation: Model

independent
2- Calculate the area for each part of the
parts 1,2,3 and 4 (until the last observed
concentration) using trapezoidal rule

1
2
3

5
46

Trapezoidal rule
(Trapezoid = )
C1

C2

C 2 C1
area
(t 2 t1 )
2
where C = concentration
t = time

t1

t2
47

AUC calculation: Model

independent
3- For part 5 (area between the last
observed concentration and infinity)
use the following equation:

C*

C*
area
K

48

AUC calculation: Model

independent
4- The total AUC (from zero to infinity) is the
sum of the areas of parts: 1,2,3,4, and 5

AUC0 AUC1 AUC2 AUC3 AUC4 AUC5

1
2
3

5
49

Fraction of the dose remaining

Fraction of dose remainig (F = X(t)/X0) is

given by the following equation:
K t

Amount at time t X 0 e
F

dose
X0

K t

since t1/2= 0.693/k, the equation can be

represented as:
t
t
0.693
1 t1 / 2
t1 / 2
Fe

250

Time to get to certain conc.

Time to get to certain concentration (C*) is

given by:

C* C 0 e

K t

C0
K t ln

C *
C0
ln

C
*

K t

C0

C*

51

Applications of one compartment

model

Case 1: Predicting Plasma Concentrations

Case 2: Duration of Action

Case 3:Value of a Dose to Give a Desired

Initial Plasma Concentration

52

Case 1: Predicting Plasma

Concentrations

A 20-mg dose of a drug was

administered as an intravenous bolus
injection. The drug has the following
pharmacokinetic parameters: k = 0.1 h1
and Vd = 20 L
1.

Calculate the initial concentration (C0 )

2.

Calculate the plasma concentration at 3 h

53

Case 1: Predicting Plasma

Concentrations
1.

Calculate the initial concentration (C 0 )

dose 20 mg
C0

1 mg/L
Vd
20 L
2.

Calculate the plasma conc. at 3 h

C C0 e

K t

1 e

-(0.1)(3)

0.74 mg/L
54

Case 2: Duration of Action

The duration of action of a drug may be

considered to be the length of time the
plasma concentration spends above the
MEC. Its determination is best illustrated
by example 2.

55

Case 2: Duration of Action

Continuing with the

drug used in Example
1, if the therapeutic
range is between 5
and 0.3 mg/L, how
long are the plasma
concentrations in the
therapeutic range?

56

Case 2: Duration of Action

As indicated in the diagram (previous

slide) C0 =1 mg/L. Thus, at time zero the
plasma concentration is in the therapeutic
range. The plasma concentration will
remain therapeutic until it falls to the MEC
(0.3 mg/L). At what time does this occur?

C0
ln

C
*

1
ln
/ 0.1 12.0 hr
57
0.3

Case 3: Value of a Dose to Give a Desired

Initial Plasma Concentration

Continuing with the drug used in

Examples 1 and 2, If the initial Cp of 1
mg/L is unsatisfactory, Calculate a dose to
provide an initial plasma concentration of
5 mg/L.
dose

C0

dose C 0 Vd

Vd
mg
dose 5
20 L 100 mg
L

58

Examples

59

Example 1

Ten mg metoclopramide was administered

intravenously to a 72 kg patient. The
minimum plasma concentration required
to cause significant enhancement of
gastric emptying is 50 ng/mL. The
following plasma concentrations were
observed after analysis of the specimen.
60

Example 1
Time (hr)

Conc. (ng/ml)

90.0

68.0

40.0

21.5

12.0

10

7.0
61

Example 1

Calculate the biological half-life of the drug

elimination (t), the overall elimination
rate constant (K), the volume (Vd), the
coefficient of distribution and the duration
of action (td)

62

Example 1
2.5

log (Conc)

y = -0.1243x + 2.0832
R2 = 0.9995
1.5

0.5

0
0

time (hr)

10

63

12

Example 1

The elimination rate constant can be

obtained from the slope:

K Slope 2.303
(0.1243) (2.303) 0.286 hr

Another way to calculate the slope is

using:

log(C1) - log(C2)
Slope
t1 - t2
64

Example 1

Another way to calculate the slope (if you do not have the
ability to do regression) is using:

log(C1) - log(C2)
Slope
- t2
where (C1,t1) and (C2,t2) are t1
two
different conc. time
points

It is important to note that the first method for calculating

the slope is more accurate
65

Example 1

Calculating the slope using the second method:

log(40) - log(21.5)
Slope
-0.13481
4-6

Note that the value of the slope is similar to the

value estimated using the first method (-0.1243)

66

Example 1

the biological half-life of the drug

elimination (t):
t 0.5

0.693 0.693

2.42 hr
K
0.286

The volume of distribution (Vd):

dose
10
10
Vd
2.0832
C0
10
121.12

mg 10 6 ng
L
0.083

3 83 L
ng/ml mg 10 ml

67

Example 1
Intercept = log (C0)
C0= 10intecept

2.5

log (Conc)

y = -0.1243x + 2.0832
2
R = 0.9995
1.5

1
y = -0.1243x + 2.0832
2
R = 0.9995

0.5

0
0

time (hr)

10

12

68

Example 1

the coefficient of distribution = Vd/wt

=83 L/ 72 kg= 1.15 L/kg

the duration of action (td). td is the time

needed for the conc. To get to 50 ng/ml :

C0
ln

C
*

121.12
ln

50

0.286
69

3.1 hr

Example 2

An adult male patient was given the first dose of an antibiotic at

6:00 AM. At 12:00 noon the plasma level of the drug was measured
and reported as 5 g/ml. The drug is known to follow the one
compartment model with a half-life of 6 hours. The recommended
dosage regimen of this drug is 250 mg q.i.d. the minimum inhibitory
concentration is 3 g/ml. Calculate the following:

Apparent volume of distribution

Expected plasma concentration at 10 AM.
Duration of action of the first dose
Total body clearance
Fraction of the dose in the body 5 hours after the injection
Total amount in the body 5 hours after the injection
Cumulative amount eliminated 5 hours after the injection
Total amount in the body immediately after injection of a second dose at 12:00 noon
Duration of action of first dose only if dose administered at 6:00 AM was 500 mg.

70

Example 2
Elimination
K 0.693

Initial

rate constant:

t 0.5

0.693 0.116 hr 1
6

concentration:

The

conc. at 12:00 noon (6 hrs after the

first dose) is 5 g/ml:

C (t 5) C0 e

k t

C (t 5)
5
C0
0.116 6 1071 ug/ml
k t
e
e

Example 2

Apparent volume of distribution:

C(t=6hrs)= 5 ug/ml. Since the half life is 6 hrs, C0
= 10 ug/ml.
X0
VD

C0

250 mg
25000 ml 25 L
-3
g 10 mg
10

ml
g

Expected plasma concentration at 10 AM

K 0.693 /t0 .5 0.693 / 6 0.1155 hr -1

C(t 4) C 0 e Kt 6.3 g/ml

72

Example 2

Duration of action of the first dose

C0

t C *
ln

10

3
ln

0.1155

10.42 hr

Total body clearance

Cl K VD 2.89 L/hr

Fraction of the dose in the body 5 hours after the

injection 5

1
F
2

0.56

73

Example 2

Total amount in the body 5 hours after the injection =

(0.56)(250 mg) = 140 mg

Cumulative amount eliminated 5 hours after the

injection = dose amount in the body = 250 140 =
110 mg

Total amount in the body immediately after injection of a

second dose at 12:00 noon
Total amount = amount from the first dose + amount from
the second dose = 125 + 250 = 375 mg

74

Example 2

Duration of action of first dose only if dose

administered at 6:00 AM was 500 mg
t d 10.42 hr 6 hr 16.42 hrs

Note that 6 hrs (one t0.5) is needed for the

amount in the body to decline from 500
mg to 250 mg
75

Example 3

The therapeutic range of a drug is 20-200 mg/L. After

an intravenous bolus injection of 1.0 gm followed by
regression analysis of the concentration of the drug in
plasma (in units of mg/L) versus time (in hours), the
following linear equation was obtained

Cp
Calculate thelog
following

2 0.1t

Duration

of action
Total body clearance
Rate of elimination at 2 hours
76

Example 3

From the equation:

log Cp 2 0.1t log(C0 ) slope t

The following were estimated:

C0 10 2 100 mg/L

K Slope 2.303 (0.1) (2.303) 0.23 hr 1

X 0 1000 mg
VD

10 L
C 0 100 mg/L
77

Example 3

Duration of action:
C0

td C *
ln

100

20
ln

0.23

7 hr

Total body clearance= KVd=(0.23)(10) =2.3 L/hr

Rate of elimination at 2 hours:
Elimination rate = Cl*C(t=2) = 2.3*63 =145 mg/hr

log(Cp(t 2)) 2 (0.1)(2) 1.8

Cp(t 2) 101.8 63 mg/L

78

79