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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 1930’s 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

ןמז תדיחיל ירמגל הפורתה תא ונאצוה וננמש יטרואית חפנ

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

-ףוגה לוכל

קימטסיס S

תוילכה לש-R

ילובטמ סנרילק-M

.

דבכה לש סנרילק H

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

המ לכ

אלש

הילכב

NR-

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

רוזיפה חפנ

עובק אוה סנרילק ילמרונ בצמ לכב

זוכירב הטילקה תמועל

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 ( זרב )

Clearance: the Tank and Faucet Model and

13

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

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 (קוליס)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 (יוצימה סחי)

• 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

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

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

→E≈1 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

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

• 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 t½

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

½

:

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 (patent’s 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 doen’t work

- if it works, it is fully functional

- if it doesn’t 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

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