Pharmacokinetics 3:

Clearance

Book Chapter 4
1

Lecture Outline

Definitions of clearance
Clearance rate and plasma
concentration
Clearance: the tank and faucet model
Physiological approach to clearance
Calculating clearance using the AUC
Creatinine clearance
The use of creatinine clearance for dose
adjustment








2
Definitions of Clearance
3
The Definition of Clearance
4
The concept of clearance is an empirical approach
developed in the 1930s to describe the functioning of
the kidney and liver in the removal of drugs from the
body
The definition of clearance is:
The volume of hypothetical fluid from which a drug is
completely and irreversibly removed per unit of time

The larger this volume is, the more efficiently the drug
is removed by the organ
Clearance gives us some idea of how organs eliminate
drugs
Description of Clearance
5
Clearance can be subdivided into:
- Systemic clearance (Cl
s
) or whole body clearance
(TBC)
- Renal clearance (Cl
r
) is the fraction of total clearance
that is removed by the kidney
- Metabolic clearance (Cl
m
) the fraction removed by
metabolism
- Hepatic clearance (Cl
H
) the fraction removed by
liver
Notice that hepatic clearance is by metabolism and
therefore, hepatic and metabolic clearance overlap
Description of Clearance
6
Clearance is often divided into renal and non-renal
clearance, where:
Cl
s
= Cl
nr
+ Cl
r

Because the liver is the most important metabolic organ,
it is often assumed that: Cl
H
~ Cl
m
~ Cl
nr

The unit of clearance are always volume/time mL/min;
mL/h
To eliminate weight variation, clearance is also expressed
per body weight: mLkg
-1
h
-1





"
Clearance Rate and
Concentration
7
Clearance and Plasma Concentration
8
In the same way that we need V
d
in order to relate
the dose to the plasma concentration, we need the
plasma concentration to relate the clearance to the
rate of excretion (mass/time)
Excretion rate = clearance x plasma concentration
Clearance and Plasma Concentration
9
This equation can be rearranged to



For the rate of elimination, this is



with total clearance instead of renal clearance
Clearance and Distribution Volume
10
Clearance is related to distribution volume V
d
using
the equation
Cl = KV
d
or K = Cl/V
d

This equation shows that under normal conditions,
the clearance is a constant
From the previous equation, we see that the
excretion is dependent on the concentration

Clearance: the Tank and
Faucet Analogy
11
Clearance: the Tank and Faucet Model and
12
One way of explaining the concept of clearance is by
using the simple model of the tank and faucet ( )


,
Clearance: the Tank and Faucet Model and
13

<

CL CP
Clearance: the Tank and Faucet Model and
14
We see that while clearance and volume are
constant, C
p
and the eliminated mass at time t dD
b
/dt
are inter-dependent and change with time
We also see why clearance is defined as the volume
from which the drug is removed completely per time
unit a drop of pure water is added to the tank for
each drop with drug that leaves the tank
We can also relate the drug mass at t=0 D
1
(an
analog of X
0
) to the concentration by using the
volume
Clearance: the Tank and Faucet Model and
15
We also see that our elimination constant K is


The equation describing the relationship between the
fraction of the drug eliminated from the tank and the
time is

The model can not show us why different drugs have
different clearance and why they have different
distribution volumes



Physiological Approach to
Clearance
16
Organ Clearance, Elimination and Extraction
17
We can describe the elimination from a single organ
as follows:





Where Q is the blood flow through the organ, C
A
is the
drug concentration in the incoming artery and Cv is
the drug concentration in the venous blood leaving the
organ

<

>

CA<CV
Organ Clearance, Elimination and Extraction
18
The rate at which the drug enters the organ is C
A
x Q
in mass/time
The rate at which the drug leaves the organ is C
V
x Q
The rate of elimination ()is the concentration
difference multiplied by blood flow = Q(C
A
-C
V
)
The clearance equals the rate of elimination divided
by the initial drug concentration



Organ Clearance, Elimination and Extraction
19
Now, we will define a new parameter: the relationship
between the rate at which the drug is delivered to the
organ and the rate at which it is eliminated:




E is the extraction ratio/fraction ( )
It describes the relative efficiency of drug elimination
at the organ it is dimentionless and has values
between 0 and 1
Organ Clearance, Elimination and Extraction
20
From our previous equations, we can also see that:
Cl
organ
= Q x E
In theory, Q, C
A
and C
V
can be measured, however,
this is not practical and all three change with time
Clearance - Examples
21
Now, we will connect all the previous equations by
using an example:
- An organ receives 10 molecules each second
- The flow rate into and out of the organ is Q=0.0125 L/s
- From this we can calculate the concentration:
(C
p
)
in
= (10 mol/s):(0.0125 L/s) = 800 mol/L
- In addition, we are given that X, the mass of drug in
the body is 1 x 10
4
mol

Clearance - Examples
22
We can now calculate V
d




Also given that from each 10 molecules that enter the
organ, 2 are metabolized
We can calculate the extraction fraction: E = 2/10 = 0.2
We have seen that the clearance is the product of the
flow Q and the E

/
Clearance - Examples
23
Further, the rate constant K is the fraction of the drug
that is metabolized per time unit



And we can connect the clearance Cl to the rate
constant using the distribution volume and the
following equation
Clearance - Examples
24
We can also use another equation to calculate the
clearance



Now we have connected all our different parameters via
the clearance and got the same value for clearance using
each method, however, few of these parameters are
time-dependent and relate in our calculation to t=1s
only (think of X, dX/dt and C
p
)
The figure in next page shows our organ (liver) in the
whole system at time t=1s
:
25
X0

Clearance - Examples
26
We know how to calculate the situation at t=1h




As expected, C
p
has decreased (from 800mol/L)
The fraction eliminated is 1- e
-kt
= 1- 0.4868 = 0.5132
So we see that in our conditions, a little more than half
of the original dose has been eliminated at 1h

=====
=====
T=0
Clearance - Examples
27
Now, we will calculate the elimination rate dX/dt
First, we nee to know what is the remaining mass at 1h:




This number is familiar because the fraction remaining
at t=1h is 0.4868 and the total mass is 10,000 mol

Clearance - Examples
28
Now, we can calculate the elimination rate:





We remember that at t=0, dX/dt was 2mol/sec, so this
is, as expected, less than half of the original, and directly
proportional to the mass and fraction remaining in body

:
Clearance - Examples
29
Now, we calculate another related parameter: the rate
of mass transport into the liver, which is (concentration
in)(flow rate):





We remember that the initial rate was 10mol/s


:
Clearance - Examples
30
The last thing we calculate here is the extraction
fraction, which is (elimination rate)/(rate drug in):





but, this is the same fraction, because the extraction
rate is a constant
....
....*
Clearance Intrinsic Clearance
31
Intrinsic clearance is defined as clearance that is not
determined by Q
H
the blood flow in the liver
The intrinsic clearance represents a measure of the
rate of enzymatic degradation of the drug

Remember that

and
where the extraction fraction is constant
In practice, E is dependent on the flow Q
organ
in
out in
organ
E Q
C
C C Q
Cl =

=
) (
Q
Cl
E
organ
organ
=

.
.

Clearance Intrinsic Clearance
32
The interdependency of E and the intrinsic clearance
is defined as: E=(Cl
int
)/(Q
H
+Cl
int
)
If Cl
int
is very large, it means that the drug is so well
metabolized so well that the organ clearance
depends almost only on the flow of blood:
Cl
int
>>Q
H
E1 and Cl
H
=QE

Cl
H
Q
H

If the drug is poorly metabolized:
Q
H
>> Cl
int
E=(Cl
int
)/(Q
H
+Cl
int
) Cl
int
/Q
H

and because Cl
H
=QE

Cl
H
Cl
int
Clearance Intrinsic Clearance
33
The equation E=(Cl
int
)/(Q
H
+Cl
int
) gives a hyperbolic
curve
E
1:1
Clearance Intrinsic Clearance
34
Notice that the intrinsic clearance is a property of the
drug, and that while the extraction ratio is dependent
on the blood flow, it is constant because the blood flow
in the liver is constant
Drugs with an extraction ratio greater than 0.7 are said
to have high intrinsic clearance, drugs with less than 0.3
have low intrinsic clearance, and drugs with values
between 0.3 and 0.7 are intermediate


. .

0.3 LINT E>0.7
Intrinsic free clearance is defined as the intrinsic
clearance of free drug, unbound to plasma proteins
We define the free clearance Cl
int
= (Cl
int
)/f
up

where f
up
is the fraction of free drug
Naturally, in drug that have large unbound fraction,
Cl
int
Cl
int


Clearance Intrinsic Clearance
35
>
If we put the substitute (Cl
int
)/(Q
H
+Cl
int
) for E in the
equation describing hepatic clearance, we get:




Now we substitute Cl
int
f
up
for Cl
int
:




Clearance Intrinsic Clearance
36
Clearance Intrinsic Clearance
Why did we do this exercise ??

Because we now have in one equation all the
independent parameters that determine the hepatic
clearance of one drug in one patient

37
Organ Clearance and Elimination t
38
In the next slides, we will connect what we have
learned about hepatic clearance to other clearance
parameters in the body
First, we will combine several equations to show the
relation of the last equation to t

:




where Cl
R
is the renal clearance
Calculating Clearance Using
the AUC
39
Systemic Clearance
40
We already know that the systemic clearance:




Now, we will integrate this equation between t=0 and
t=:


Systemic Clearance
41
So, for the systemic clearance after bolus injection:
Cl
s
= dose/(AUC)
0

where AUC is the area under the
plasma concentration curve between times 0 and
infinite

Renal Clearance
42
The renal clearance can be calculated using several
methods
Method 1
Cl
r
= K
u
V
d
- where K is the elimination constant in urine

Method 2
Cl
r
= (X
u
)

/(AUC)
0

where X is the mass excreted
unchanged in urine
Renal Clearance
43
Method 3
Cl
r
= (fraction excreted unchanged) x (dose) /(AUC)
0

which is very similar to method 2
Method 4





This is easy to estimate if we measure both at time t
Metabolic Clearance
44
Also the metabolic clearance can be determined using
several methods
Method 1
Cl
m
= K
m
V
d
where K is the metabolic rate constant

Method 2
Cl
m
= (M
u
)

/(AUC)
0

where M is the mass of
metabolite (if there is only 1) excreted in urine





This is easy to estimate if we measure both at time t
Metabolic Clearance
45
Method 3
Cl
m
= (fraction metabolite in urine) x (dose) /(AUC)
0

Notice that even if the drug is both metabolized and
excreted unchanged in urine, we only need to know
two of the three clearance (systemic, metabolic, urine)
because:
Cl
s
= Cl
r
+ Cl
m
Creatinine Clearance
46
Mechanism of Elimination in Kidney
47
The appearance of a drug in the urine, or rate of
excretion, is determined by 3 factors:

- Rate of filtration
- Rate of (active) secretion
- Rate of (active) reabsorption

If a drug has no secretion or reabsorption, then:
rate of excretion = rate of filtration , and
renal clearance (Cl
r
) = f
u
x GFR where GFR is glomerular
filtration rate and f
u
is the fraction of unbound drug

Creatinine and Inulin
48
Ceatinine (see picture) and inulin (a polysaccharide)




are not bound to plasma protein, not reabsorbed or
excreted in the kidney (also no metabolism) and
therefore are used to determine the functioning of the
kidney
Inulin is an exogenous molecule, while creatinie is and
endogenous end product of muscle metabolism
Creatinine Clearance
49
Ceatinine is an endogenous molecule. Therefore, it
does not have to be administered, but must be
measured in the blood
Normal values are:
- Clearance: adult males: 120 20 mL/min
adult female: 108 20 mL/min
- Serum concentration: adult males: 8-13 mg/L
adult females: 6-10 mg/L
For both inulin and creatinine, the clearance is
approximately equal to the glomerular filtration rate
Creatinine Clearance
50
GFR is 125-130mL/min in healthy adults
GFR depends on body mass, degree of activity, muscle
mass and age
It is essential to determine the renal function in many
situations, like in elderly or seriously ill, when the drug
is given IV and has a narrow therapeutic window
Calculating Creatinine Clearance
51
Creatinine clearance is measured as follows:
- A urine sample(s) is collected over an interval and the
mass excreted in urine is calculated from urine
volume x concentration in sample(s)
- Blood samples are collected and the mean serum
concentration over the period of urine collection
is calculated
- The directly measured (Cl
s
)
cr
is calculated using the
equation

Calculating Creatinine Clearance
52
In most cases, ceratinine in urine is collected over
24h=1440min
Because creatinine levels in plasma are relatively
stable, 1 blood sample is taken at any convenient time
within the 24h
Many times, it is impossible or impractical to collect
urine samples in these situation, only serum
creatinine is measured and kidney function is estimated
from the serum creatinine alone

Calculating Creatinine Clearance
53
There are at least 10 different equations used to adjust
the relation between serum creatinine and actual renal
clearance of creatinine to: age, gender, body fat (>30%
of lean mass) and patients suffering from renal failure
These are all empirical formulas based on measured
values rather than on theoretical considerations
An example :


This is the equation used for adult men C
s
is in
mg/100mL
( ) | | % 72
) 140 ( ) (
mg C x
age x kg Weight
Cl
cr
s
cr

=
Significance of Creatinine Clearance
54
Usually, normal creatinine clearance indicate the the
kidney is functioning as it should
In elderly and in some disease states, the creatinine
clearance is likely to be reduced
For these patients, it is necessary to adjust the dose
and or the dosing regimen (dose drug per pill and/or
number of doses per day)
Because creatinine clearance affects the systemic
clearance and elimination, it is expected to affect all PK
parameters (with exception of V
d
and related
parameters)
Cl
cr
effect on drug clearance

55
Bolus injection in a one compartment model follows
the equations:



The graph on the following slide shows the effects of
different degrees of renal dysfunction on the relation of
C
p
/t
Notice that V
d
and C
p
(which is product of X
0
and C
p
are
not affected
Cl
cr
effect one drug clearance

56





Cl
cr
effect one drug clearance

57
In an single extravascular dose (oral or other), the
relationship may look like in the graph below
Cl
cr
effect one drug clearance

58
In practice, the effect of Cl
cr
or GLF is very much
dependent of the mechanism of elimination and varies
greatly
KN/Knr (%)


K
nr
(per h) K
N
(per h) Drug
92.3 0.36

0.39 Lidocaine
71.8 0.28 0.39 Erythromicin
50.0 0.60 1.20 Dicloxacillin
14.3 0.10 0.70 Amoxicillin
5.0 0.015 0.30 Gentamicin
Cl
cr
effect one drug clearance

59
Another example shows the relationship between
creartinine clearance and serum half-life for two drugs
The Use of Creatinine Clearance
for Dose Adjustment
60
Cl
cr
Examples for Use

61
The table below shows the relation between creatinine
clearance, drug plasma half-life and drug clearance for
the antiviral drug acyclovir, used for example for herpes
simples virus infection renal clearance is 62-92%
Cl
cr
Examples for Use

62
The table below shows the adjustment of the
recommended dose and dosing regimen according to
the creatinine clearance of ceftazidime a
cephalosporin antibiotic
Cl
cr
Examples for Use

63
Sometimes, we use a
diagram to calculate the
dose reduction according
to the creatinine
clearance
The table on the right
shows the adjustment
diagram tobramycin
another antibiotic
Notice that creatinine
clearance can also be
derived from C
cr

Cl
cr
Examples for Use

64
In drugs that are eliminated exclusively (or almost
exclusively) by the kidney, we can use a simple
equation to calculate the dose-adjustment using the
creatinie clearance:
Adjusted daily dose = (X
0
)
NR
x (patents ceratinine
clearance)/Normal creatinine clearance


Cl
cr
The Intact Nephron Hypothesis

65
Calculations where creatinine clearance is used are based
on the assumption that even if the drug is actively
absorbed or excreted, drug clearance is directly
proportional to the creatinine clearance
This assumptions is called the intact nephron hypothesis:
- a nephron either works or doent work
- if it works, it is fully functional
- if it doesnt work, filtration, active and passive
reabsorption and excretion are equally dysfunctional
- both creatinine clearance and drug clearance are
proportional to the fraction of functioning nephrons