One Compartment

Model
)Intravenous Bolus(

2023 - 1444 1
Outcomes & Objectives
Related learning outcome:
 Outline the different pharmacokinetic models.

 Calculate the relevant pharmacokinetic parameters of drugs following diverse

models given by different routes.

Lecture Objectives:
 Understand the pharmacokinetic parameters of the one-compartment model
following IV bolus.

 Calculate the different parameters of the one-compartment model following IV

bolus.

2
One compartment IV bolus
 The one-compartment open model assumes that the body acts like a single,
uniform compartment and the drug can enter or leave the body (ie, the model is
"open").

 When IV bolus of a drug is given, the entire dose of drug enters the bloodstream
immediately, and the drug absorption process is considered to be instantaneous.

 The drug distributes instantaneously via the circulatory system to all the tissues in
the body.

 Because of rapid drug equilibration between the blood and tissue, drug elimination
occurs as if the dose is all dissolved in a tank of uniform fluid (a single
compartment) from which the drug is eliminated.

 The volume in which the drug is distributed is termed the apparent volume of
distribution (VD) The apparent volume of distribution assumes that the drug is
uniformly distributed in the body.

3
One compartment IV bolus

The pharmacokinetic parameters of the one-compartment model

include:

1. The apparent volume of distribution (VD), which governs the plasma

concentration of the drug after a given dose.

2. The elimination rate constant (k), which governs the rate at which the drug
concentration in the body declines over time.

4
One compartment IV bolus

The one compartment model that describes the distribution and elimination
after an IV bolus dose is given in (Fig. 1).

 Fig. 1: Pharmacokinetic model for a drug

administered by rapid intravenous injection.

DB = Drug in body.
VD = Apparent volume of distribution.
k = Elimination rate constant.

 The one-compartment open model does not predict actual drug levels in
the tissues.

 However, the model assumes that changes in the plasma levels of a drug
will result in proportional changes in tissue drug levels.

5
One compartment IV bolus

I. Elimination rate constant :

 A rate expression for (Fig. 1) is:

dD B
= -k D B )1(
dt

 This expression shows that the rate of change of drug amount in the body is a
first order process, depending on;
 The overall elimination rate constant (K), with units of time-1 (e.g: hr-1 or
1/hr).
 The amount of drug in the body (DB), remaining at any given time (t).

6
One compartment IV bolus
I. Elimination rate constant :
Integration of (Eq. 1) gives the following expression:

-kt
log DB = +log DB0 (2)
2.303

Where:
DB = drug in the body at time t.
D0B = drug in the body at t = 0.

 When log DB is plotted against t for this equation, a

straight line is obtained (Fig. 2).

 In practice, instead of transforming values of DB to their

corresponding logarithms, each value of DB is placed at Semi-log graph of the rate of drug
logarithmic intervals on semi-log paper. elimination in a one-compartment
model.
7
One compartment IV bolus
I. Elimination rate constant :
Equation (2) can also be expressed as:

-kt
DB = DB e
0 (3)

 The amount of drug in the body is not determined directly. Instead, a blood sample is
removed at periodic intervals and analyzed for its concentration of drug.

 An expression based on drug concentration in plasma is obtained for the first-order

decline of drug plasma levels:

-kt
log p = +log C 0
p (4)
C 2.303

C p = Cp -kt (5)
0 8
One compartment IV bolus
I. Elimination rate constant :

ln C = ln C 0-
(6)

kt P P
The half-life (t1/2) can be calculated from:

0.693
t1 / 2 = (7)
k

9
One compartment IV bolus
I. Elimination rate constant :

 Total elimination of the parent drug from this compartment is effected by

metabolism (biotransformation) and excretion.
 In such a case, each of these processes has its own first-order rate
constant.
 The elimination rate constant represents the sum of each of these
processes:
K= Km + Ke (8)

 where km = first-order rate constant of metabolism.

 ke = first-order rate constant of excretion.

10
One compartment IV bolus
II. Apparent volume of distribution:

 The amount of drug in the body can be related to its concentration by a

proportionality constant that reflects the volume of fluid in which the drug is
dissolved.
 This is called the volume of distribution.
 Because the value of the volume of distribution does not have a true
physiologic meaning in terms of an anatomic space, the term apparent volume
of distribution (VD) is used.
 The VD must be considered in estimating the amount of drug in the body (DB)
from the concentration of drug found in the sampling compartment as in the
following equation:

DB = VD Cp (9)

11
One compartment IV bolus
II. Apparent volume of distribution:
1. Calculation of volume of distribution:
In a one-compartment model (IV administration), when C0 is determined by
p
extrapolation, it represents the instantaneous drug concentration (concentration of
drug at t = 0) after drug equilibration in the body (Fig. 3).

Fig. 3: Semi-log graph giving the value of C0 p

by extrapolation. 12
One compartment IV bolus
II. Apparent volume of distribution:
1. Calculation of volume of distribution:
The dose of drug given by IV bolus (rapid IV injection) represents the amount of
drug in the body, , at t = 0. Because both D0 and C0 , are known at t = 0, then
the apparent volume of distribution (VD), may be calculated from the following
equation:

Dose o
Vd = = DB (10)
C P0 Co
p

Also, the apparent VD can be calculated by means of (Eq. 11):

D0
VD = (11)
K[ AUC]0
13
One compartment IV bolus
II. Apparent volume of distribution:
1. Calculation of volume of distribution:
The calculation of the apparent VD by means of (Eq. 11) is a model independent
method, because no pharmacokinetic model is considered.

The AUC is determined directly by the trapezoidal rule using the following
equation.

(C
AUC C p dt CPn 1 ) Cp (12)
0 0 pn . t
0 last

2 K

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One compartment IV bolus
II. Apparent volume of distribution:
2. Significance of the apparent volume of distribution:

a) In general, the value of the apparent volume of distribution gives an indication about
the binding affinity of drug.

Most drugs have an apparent volume of distribution smaller than, or equal to, the body
mass. For some drugs, the volume of distribution may be several times the body mass.
As shown in (Eq. 10), the apparent VD is dependent on C0 .
p

15
One compartment IV bolus
II. Apparent volume of distribution:
2. Significance of the apparent volume of distribution:

 For a given dose, a very small C0 pmay occur in the body due to concentration of the
drug in peripheral tissues and organs which will result in a large VD. The larger the
apparent VD, the greater is the amount of drug in the extravascular tissues.
 If a drug is highly bound to plasma proteins or remains in the vascular region,
then
C0 p
will be higher, resulting in a smaller apparent V D. The smaller the V D, the greater
is the amount of drug in the vascular system.

b) Given the apparent VD for a particular drug, the total amount of drug in the body at
any time after administration of the drug may be determined by the measurement of
the drug concentration in the plasma (Eq. 9).

16
One compartment IV bolus
II. Apparent volume of distribution:
2. Significance of the apparent volume of distribution:

c) The apparent VD is a volume term that can be expressed as a simple volume or in

terms of percent of body weight. (In expressing the apparent VD in terms of percent
body weight, a 1-L volume is assumed to be equal to the weight of 1 kg).
For example: if the VD is 3500 mL for a subject weighing 70 kg, the VD expressed as
percent of body weight is 3 . 5 k g = 5 % of body weight.
x 1 0 0
7 0 k g

d) For each drug, the apparent VD is a constant. In certain pathologic cases, the
apparent VD for the drug may be altered if the distribution of the drug is changed.

17
One compartment IV bolus
III. Clearance:
Clearance: is a measure of drug elimination from the body without identifying the
mechanism or process.

 Clearance (drug clearance, systemic clearance, total body clearance (ClT)) considers
the entire body as a drug-eliminating system from which many elimination
processes may occur.
 Drug clearance refers to the volume of plasma fluid that is cleared of drug per unit
time  volume/unit time (e.g: L/hr or mL/min).

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One compartment IV bolus
III. Clearance:

1. Clearance and Volume of Distribution Ratio (Cl/VD):

The first-order elimination rate constant is the fractional constant Cl/VD

Cl
k = (13)
V D

2. Clearance from drug eliminating tissues:

 Clearance may be applied to any organ that is involved in drug elimination from the
body.

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One compartment IV bolus
III. Clearance:
2. Clearance from drug eliminating tissues:
 Clearance represents the sum of the clearances for each drug-eliminating organ as
shown in (Eq. 14):

ClT = ClR + ClNR (14)

Where: ClR = Renal clearance or drug clearance through the kidney.
ClNR = Is nonrenal clearance through other organs.

 ClNR is assumed to be due primarily to hepatic clearance (ClH) in the absence of

other significant drug clearances, such as elimination through the lung or the bile, as
shown in (Eq. 15):

ClT = ClR + ClH (15)

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One compartment IV bolus
III. Clearance:
2. Clearance from drug eliminating tissues:
 ClT may be also be defined as the rate of drug elimination divided by the plasma
drug concentration.

elimination ratet Or
Cl
T= plasma concentratiom (CP )

Where: DE = the amount of drug eliminated.

dDE /dt = The rate of drug elimination.

Or
dD E
D r u g elimin ation rate = C PClT (16)
dt

Therefore, ClT is a constant for a specific drug and represents the slope of the line
obtained by plotting dDE /dt versus Cp as shown in (Eq 16).
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One compartment IV bolus
III. Clearance:
2. Clearance from drug eliminating tissues:
 As the plasma drug concentration decreases during elimination, the rate of drug elimination
(dDE /dt) will decrease accordingly, but clearance will remain constant. Clearance will be
constant as long as the rate of drug elimination is a first-order process.

 For some drugs, the elimination rate process is more complex and a non compartment
method may be used to calculate certain pharmacokinetic parameters such as clearance. In
this case, clearance can be determined directly from the plasma drug concentration-versus-
time curve using this eq.:
D0
Cl T = (17)
Where: D0 = Dose. [ A U C ]0
[ AUC =
]0
Because [ AUC]0 is calculated from the plasma drug concentration-versus-time curve from 0 to
infinity (∞) using the trapezoidal rule, no compartmental model is assumed. If the drug follows the
kinetics of a one-compartment model, the ClT is numerically similar to the product of VD and k
obtained by fitting the data to a one-compartment model. 22
Example (1):
A new drug was given in a single intravenous dose of 200 mg to an 80-kg
adult male patient. After 6 hours, the plasma drug concentration of drug was
1.5 mg/100 mL of plasma. Assuming that the apparent VD is 10% of body
weight, compute the total amount of drug in the body fluids after 6 hours.
What is the half-life of this drug?
drug in the body (DB )
Answer: VD =
Cp
D0 = 200 mg
VD = 10% of body weight = 0.1 (80 kg) = 8000 mL = 8 L -kt
log B= +log D 0B
At 6 hours: C P = 1.5 mg/ 100 D 2.3
ml
Then: K = 0.085 hr-1

DB = CPVD = 1.5 mg (8000 ml)= 120

100 mg
ml
-k (6)
log120 = + log
200
2.3

t1 / = 0.693 = 0.693 8.1hr

2
k 0.085 23
… Example (2):
.
A 70-kg volunteer is given an intravenous dose of an antibiotic, and serum
drug concentrations were determined at 2 hours and 5 hours after
administration. The drug concentrations were 1.2 and 0.3 µg/mL,
respectively. What is the biologic half-life for this drug, assuming first-order
elimination kinetics?
-kt
log p = +log Cp
Answer: 2.3 0
C
The CP decreased from 1.2 to 0.3 µg/mL in 3 hours.
k = 0.462 hr-1
t1/2 = 1 .5hr
t (hr) Cp (ug/ml)
2 1.2
5 0.3
-k(3)
log 0.3 = log1.2
2.3

0.693 0.693
t1 / = =0.462
2 k
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CALCULATION OF k FROM URINARY
EXCRETION DATA
Determination of KE from Urinary Excretion Data can be
computed from urine data by two methods:
1. Rate of excretion method
2. Sigma-minus method.
Rate of excretion method
The elimination rate constant k may be calculated from
urinary excretion data. In this calculation the excretion
rate of the drug is assumed to be first order. The term ke
is the renal excretion rate constant, and Du is the amount
of drug excreted in the urine.
:From Equation DB can be substituted for DB 0 e–kt

Taking the natural logarithm of both sides and then transforming

to common logarithms, the following expression is obtained
There are practical considerations of collecting urine for
drug analysis since urine is produced at an approximate
rate of 1 mL/min and collected in the bladder until
voided for collection. Thus, the drug urinary excretion
rate (dDu/dt) cannot be determined experimentally for
any given instant. In practice, urine is collected over a
specified time interval, and the urine specimen is
analyzed for drug. An average urinary excretion rate is
.then calculated for that collection period
Therefore, the average rate of urinary drug excretion,
Du/t, is plotted against the time corresponding to the
midpoint of the collection interval, t*, for the
collection of the urine sample. The average value of
dDu/dt is plotted on a semilogarithmic scale against
the time that corresponds to the midpoint (average
.time) of the collection period
A single IV dose of an antibiotic was given to a 50-kg
woman at a dose level of 20 mg/kg. Urine and blood
samples were removed periodically and assayed for
:parent drug. The following data were obtained

What is the elimination rate constant, k, for this

antibiotic?
:Solution Set up the following table

Here t* = midpoint of collection period and t = time interval for

.collection of urine sample
Construct a graph on a semilogarithmic scale of Du/t
versus t*. The slope of this line should equal –k/2.3. It
is usually easier to determine the elimination t½
directly from the curve and then calculate k from
In this problem, t1/2 = 1.0 hour and k = 0.693 h–1.
Note that the slope of the log excretion rate constant
is a function of the elimination rate constant k and
not of the urinary excretion rate constant ke

A similar graph of the Cp values versus t should yield

a curve with a slope having the same value as that
derived from the previous curve. Note that this
method uses the time of plasma sample collection,
not the midpoint of collection
sigma-minus method, or the amount of drug remaining
to be excreted method
The sigma-minus method is sometimes preferred over the
previous method because fluctuations in the rate of
elimination are minimized. The amount of unchanged
drug in the urine can be expressed as a function of time
:through the following equation

where Du is the cumulative amount of unchanged

drug excreted in the urine.
The amount of unchanged drug that is ultimately excreted
in the urine, Du ∞, can be determined by making time t
equal to ∞. Thus, the term e–kt becomes negligible and
:the following expression is obtained

Substitution of Du ∞ for keD0/k in Equation and

rearrangement yields
Equation can be written in logarithmic form to obtain
:a linear equation

Equation describes the relationship for the

amount of drug remaining to be excreted
versus time. A linear curve is obtained by
graphing the logarithm scale of the amount of
unchanged drug yet to be eliminated, log
versus time. On semilog paper, the slope of this
curve is –k/2.3 and the y intercept is
Sigma-minus method, or the amount of drug remaining to be excreted
method, for the calculation of the elimination rate constant according to
Equation
Using the data in the preceding problem, determine the
:elimination rate constant. Solution Construct the following table
Comparison of the Rate and the Sigma-Minus Methods
The rate method is highly dependent on the accurate-1
measurement of drug in the urine at each time point.
Fluctuations in the rate of drug elimination and
experimental errors including incomplete bladder emptying
for a collection period cause appreciable departure from
linearity using the rate method, whereas the accuracy of
the sigma-minus method is less affected.
2-The rate method is applicable to zeroorder drug
elimination process, while the sigmaminus method is not.
Lastly, the renal drug excretion rate constant may be
obtained from the rate method but not from the sigma-
.minus method
The sigma-minus method requires knowing the Du ∞-3
and even a single missed urine collection will invalidate
the entire urinary drug excretion study. This method
also requires the collection of urine until urinary drug
excretion is complete; prematurely ending the study
early will invalidate the study. Finally, a small error in
the assessment of Du ∞ introduces an error in terms of
curvature of the plot, because each point is based on
log versus time
Problems in Obtaining Valid Urinary Excretion Data

Certain factors can make it difficult to obtain valid urinary

excretion data. Some of these factors are as follows
A significant fraction of the unchanged drug must be .1
excreted in the urine.
2. The assay technique must be specific for the
unchanged drug and must not include interference due
to drug metabolites that have similar chemical
.structures
Frequent sampling is necessary for a good curve .3
.description
Urine samples should be collected periodically .4
until almost all of the drug is excreted. A graph of the
cumulative drug excreted versus time will yield a
curve that approaches an asymptote at “infinite” time
(Fig). In practice, approximately seven elimination
half-lives are needed for 99% of the drug to be
.eliminated
 Graph showing the cumulative urinary excretion of drug as a
.function of time

Variations in urinary pH and volume may cause .5

.significant variation in urinary excretion rates
Subjects should be carefully instructed as to the .6
necessity of giving a complete urine specimen (ie,
completely emptying the bladder)