This document discusses clearance concepts in pharmacokinetics. It defines clearance as the proportionality constant relating the rate of drug elimination to its concentration in blood or plasma. Clearance depends on blood flow and the extraction ratio of the clearing organ. The two main types of clearance are hepatic clearance and renal clearance. Renal clearance can be estimated by measuring creatinine clearance. The document provides equations for calculating clearance, area under the curve, and creatinine clearance and adjusting drug doses based on renal function.

1. Clearance Concept
Anas Bahnassi PhD RPh

2. Lecture Objectives
After the completion of this lecture the student
should be able to:
1. Define clearance and extraction ratio and describe the relationship
between them.
2. Distinguish clearance from elimination rate and elimination rate
constant.
3. Explain the dependence of elimination half life on apparent
volume of distribution and clearance
4. Calculate area under the plasma drug concentration versus time
curve by use of the trapezoidal rule and by other methods
5. Calculate a patient’s creatinine clearance using the appropriate
equation
6. Calculate dosing adjustments of a renally excreted drug in
patients with various degrees of renal impairment (dysfunction).

3. A Physiological Approach to
Understand Clearance
Concept Site of
Action
Heart
Clearing Organ
(Pump)
(Kidney/Liver)
The blood exiting the eliminating
organ has a lower concentration
than the blood entering the organ.
The efficiency of Removal is
quantified by the Extraction Ratio
[ER].

4. Extraction Ratio
Extraction Ratio can be defined
as the proportion of drug removed
during passage through the organ.
Ca
Cv
−
=

5. Clearance
A proportionality constant describing
the relationship between a
substance’s rate of elimination
(amount per unit time) at a given time
and its corresponding concentration
Clearance in an appropriate fluid at that time.
is: The hypothetical volume of blood
(plasma or serum) or other
biological fluids from which the
drug is totally and irreversibly
removed per unit time.’
Organ clearance = Blood flow rate X Extraction ratio
= .

6. Hepatic
Types of Clearance
Clearance Renal
Clearance
The clearance of drug (a
Metabolic fraction of total clearance)
Clearance for a drug that is removed
from the blood
This is the total of every (plasma/serum) by
individual organ clearances the process of renal
that contribute to the excretion.
elimination of drugs.
However, the organ clearance
that can be routinely
determined independently in
humans is renal clearance = +
because this is the only organ
for which we can easily
determine an elimination
rate.

7. Clearance is a proportionality constant that relates rate
of elimination (rate of excretion in renal clearance) to
Plasma (or serum) concentration at any given time
=
=
=

8. Elimination half-life
vs. Clearance
0.693
= ½ =
0.693
½ =
Elimination half life is dependent on the
volume of distribution and total clearance

9. Calculating Clearance
IV Bolus =
Clearance for the entire dose can be
obtained by integrating the right hand side
of the equation from t=0 to t=
=∞
()
= =
. ℎ
=0

10. Calculating AUC
IV Bolus
s
+
Area = 2

11. Calculating AUC
Trapezoidal Rule:
C1 or concentration1
C2 or concentration2
t1 or time1
t2 or time2
Area = ((C1 + C2)/2)(t2 – t1)

12. =∞ Calculating AUC
. Trapezoidal Rule:
=
C1 or concentration1
C2 or concentration2
t1 or time1 t2 or time2
=∞
. = Area = Sum individual trapezoids
= =(((C1 + C2)/2)(t2 – t1))

13. =∞
.
Calculating AUC
= Trapezoidal Rule:
C1 or concentration1
C2 or concentration2
∞

t1 or time1 t2 or time2
=∞
. =
=

14. Creatinine Clearance
Creatinine clearance (Clcr) is renal clearance (Clr) applied
to endogenous creatinine ( a product of muscles
metabolism). It is used to monitor renal function and is a
valuable parameter for calculating dosage regimens in
elderly patients or those suffering from renal dysfunction.
Normal creatinine clearance (Clcr) values are:
• Adult males: 120±20mLmin-1
• Adult females: 108 ±20mLmin-1.

15. Creatinine Clearance
Direct measurement of Creatinine clearance
Rate of
∆ Creatinine
Excretion
∆
=
( )
Creatinine Serum
Concentration

16. Creatinine Clearance
Indirect measurement of Creatinine clearance
Males:
ℎ() × (140 − )
=
72 × (%)
Females:
ℎ() × (140 − )
= 0.85
72 × (%)

17. Creatinine Clearance
The significance of Creatinine clearance
1. Normal Creatinine clearance usually indicates normal
kidney function
2. Creatinine clearance changes with age, physiological
states, or other medical conditions and dose need to
be changed accordingly
3. Dose frequency can be changed instead of changing
the dos amount.
4. Changes in Creatinine clearance cause pharmacokinetic
parameters to change.

18. Question 1
The table shows the concentration data vs
Time Cp (ug/mL)
time for Cinoxacin after IV bolus
(hr) administration. Plot the data and use the
graph to obtain the followings:
0.25 11.6±1.3
1. Elimination half-life (t½)
0.5 8.4±1.0 2. Elimination rate constant (k)
0.75 7.2±1.1 3. Apparent volume of distribution
1 6.1±1.1 4. Systemic clearance (Cls)
1.5 4.2±1.0 5. ∞
0
2 3.2±0.9 6. Urine samples over 24 h showed the
percentage of the administered dose
3 1.9±0.7
recovered unchanged was 50.1%. The rest
4 1±0.4 were metablolites. Determine the renal
6 0.3±0.2 clearance (Clr), metabolic clearance (Clm),
8 0.09±0.1 the excretion rate constant (Ku), and the
metabolite rate constant (Km).

19. Plasma Concentration vs time
Rectilinear Paper
14
12
Plasma Concentration (ug/mL)
10
8
6
4
2
0
0 1 2 3 4 5 6 7 8 9
Time (h)

20. Plasma Concentration vs time
Semilog Paper
100
Plasma Concentration (ug/mL)
t½=1.2h
10
K=0.577h-1
V=20.833L
Cls=12.02L/h
AUC=20.797u
1 g/mL
0 1 2 3 4 5 6 7 8 9
Ku=0.298h-1
Km=0.287h-1
0.1
0.01
Time (h)

21. Pharmacokinetics
Anas Bahnassi PhD RPh
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