Clearance
From A Physiologic Perspective
Chemical Clearance from the Body
Objectives for Today
•Problems / Questions & Review concerning
Chemical Distribution …?
•A Physiologic View of
Chemical Clearance from the Body
• Develop a definition for Clearance.
Clearance
With time, where does the drug go?
Why are drugs lost from the body?
How are drugs lost from the body?
Based on random flow?
Like the elimination of an
coloured gas or odour from a room
or …?
Blood Flows1
Tissue
or
Organ
Weight
(kg)
%
of
IBW
Kidneys
Adrenals
Thyroid
Brain
Liver
Muscle
Skin
Fat
0.16
0.011
0.03
1.35
1.5
28
18
10
0.23
0.02
0.04
1.93
2.14
40
26
15
Blood % Cardiac
Flow
Output3
(mL/min)
1200
65
165
729
3002
850
260
105
23
1.2
3.2
14
5.8
16
5.0
2.0
1. Spector, WS. Handbook of Biological Data
2. Includes only arterial flow; total equals about 1500 mL/min. (25%)
3. Cardiac Output / 70 kg = 5-6 L/min [85 mL/min/kg]
Clearance
With time, where does the drug go?
Organs are strategically arranged
(liver – to deal with entry & elimination
of compounds and are well perfused tissues.
If a drug is eliminated by an organ
(kidney or liver),
the organ will have access to a greater
amount of drug if a larger percentage of drug
is found in the blood / plasma or serum.
Theophylline 9.8%
Levo: 3.5% / 4.2%
Cipro: 2.9 %
Cyclosporin: 0.15%
Clearance
With time, where does the drug go?
Organs are strategically arranged
(liver – to deal with entry & elimination
of compounds and are well perfused tissues.
The blood emerging
from an eliminating organ
has a lower concentration
than the blood entering the organ.
This effectively dilutes
the drug concentration
in the primary storage area
… the rest of the body.
Focus on an Eliminating Organ
Pump
Clearing Chamber
Blood leaving the organ has a lower
drug concentration than drug entering.
Drug is “cleared” by the organ.
The efficiency of Removal is
quantified by the Extraction Ratio [ER].
Focus on an Eliminating Organ
Ca
Cv
Extraction Ratio can be viewed
as the proportion of drug removed
during passage through the organ.
Focus on an Eliminating Organ
Ca
Cv
Extraction Ratio can be viewed
as the proportion of drug removed
during passage through the organ.
At constant concentration (steady – state)
extraction can be estimated from the
difference between arterial and venous concentrations.
ER = [ (Ca – Cv) / Ca ]
where Ca is the concentration
in the artery on entry to the organ
and and Cv is the concentration
in the vein on exit from the organ
Focus on an Eliminating Organ
Pump
Clearing Chamber
Clearance of drug is dependant on 2 factors:
Efficiency of Removal [ER]
and
The rate at which drug can be
delivered to the organ [Flow Rate: Q].
Clearance = Q x ER (mL/min)
Focus on an Eliminating Organ
At constant concentration (steady – state)
clearance can be estimated from blood flow
and the difference between
arterial and venous concentrations.
ClH = Q [ (Ca – Cv) / Ca ] = Q*ER
or
Cl = Q x ER
where ER is the Extraction Ratio
and Q is organ blood flow.
When we focus on a single organ,
Hepatic Clearance would be symbolized by ClH
and Renal Clearance by CLR
Focus on an Eliminating Organ
When we focus on a single organ,
Hepatic Clearance would be symbolized by ClH
and Renal Clearance by CLR …
ClTOTAL = ClHEPATIC + ClRENAL + ClLUNG
Clearance as the units of Volume per time
(mL/min)
Definition:
Clearance:
The volume of distribution volume of the sampled fluid
from which drug is irreversibly removed per unit time.
Focus on an Eliminating Organ
How Efficient is a Normal Kidney
in removing Creatinine?
Cardiac Output = 85 mL/kg/min 70 kg male
Creatinine Clearance = ~ 120 mL/min (serum)
Q
R
BLOOD
= 25% CO
Focus on an Eliminating Organ
How Efficient is a Normal Kidney
in removing Creatinine?
Cardiac Output = 85 mL/kg/min 70 kg male
Creatinine Clearance = ~ 120 mL/min (serum)
Q
R
BLOOD
Equations
Conc = Dose / V
V = Dose/Conc
Cl = Q x ER
ER = Cl / Q
Q
R
SERUM
= 25% CO
= 0.25 (85)
= 21.25 mL/min/kg
=
Q
R
BLOOD
Focus on an Eliminating Organ
How Efficient is a Normal Kidney
in removing Creatinine?
Cardiac Output = 85 mL/kg/min 70 kg male
Creatinine Clearance = ~ 120 mL/min (serum)
Q
R
BLOOD
Equations
Conc = Dose / V
Q
R
SERUM
V = Dose/Conc
Cl = Q x ER
ER = Cl / Q
ER
= 25% CO
= 0.25 (85)
= 21.25 mL/min/kg
Q
BLOOD (0.55)(70)
=
R
= 820 mL/min (serum)
=
Focus on an Eliminating Organ
How Efficient is a Normal Kidney
in removing Creatinine?
Cardiac Output = 85 mL/kg/min 70 kg male
Creatinine Clearance = ~ 120 mL/min (serum)
Q
R
BLOOD
Equations
Conc = Dose / V
Q
R
SERUM
V = Dose/Conc
Cl = Q x ER
ER = Cl / Q
ER
= 25% CO
= 0.25 (85)
= 21.25 mL/min/kg
Q
BLOOD (0.55)(70)
=
R
= 820 mL/min (serum)
= 120/820 = 0.146
or 14.6%
Focus on an Eliminating Organ
How Efficient is a Normal Kidney
in removing Ciprofloxacin?
Cardiac Output (Renal)= 820 mL/min (serum)
Cipro Clearance
= 35 L/hour (serum)
=
Equations
Conc = Dose / V
V = Dose/Conc
Cl = Q x ER
ER = Cl / Q
Focus on an Eliminating Organ
How Efficient is a Normal Kidney
in removing Ciprofloxacin?
Cardiac Output (Renal)= 820 mL/min (serum)
Cipro Clearance
= 35 L/hour (serum)
= 583 mL/min
Equations
Conc = Dose / V
V = Dose/Conc
Cl = Q x ER
ER = Cl / Q
Q
R
SERUM
=
Q
R
BLOOD
Focus on an Eliminating Organ
How Efficient is a Normal Kidney
in removing Ciprofloxacin?
Cardiac Output (Renal)= 820 mL/min (serum)
Cipro Clearance
= 35 L/hour (serum)
= 583 mL/min
Equations
Conc = Dose / V
V = Dose/Conc
Cl = Q x ER
ER = Cl / Q
Q
R
SERUM
ER
Q
BLOOD (0.55)(70)
=
R
= 820 mL/min (serum)
=
Focus on an Eliminating Organ
How Efficient is a Normal Kidney
in removing Ciprofloxacin?
Cardiac Output (Renal)= 820 mL/min (serum)
Cipro Clearance
= 35 L/hour (serum)
= 583 mL/min
Equations
Conc = Dose / V
V = Dose/Conc
Q
R
SERUM
ER
Q
BLOOD (0.55)(70)
=
R
= 820 mL/min (serum)
= 583/820 = 0.71
or 71%
Cl = Q x ER
ER = Cl / Q
Very efficient
Male Acute Community
Acquired Pneumonia
Equations
Conc = Dose / V
V = Dose/Conc
Cl = Q x ER
ER = Cl / Q
Physiologic Approach
to Cipro Pharmacokinetics
Male with Pneumonia
Given the clearance of ciprofloxacin,
how much drug is required each day
to maintain an average concentration
of 2 mg/L? (peaks of 3-4; troughs ~0.5)
Age:
45 yr
Weight:
80 kg
Drug:
Ciprofloxacin
Serum ciprofloxacin concentrations
average 2 g/mL (mg/L)
Cipro Volume:
1.5 L/kg
Cipro Am’t in body:
Cipro Clearance:
Male Acute Community
Acquired Pneumonia
Equations
Conc = Dose / V
V = Dose/Conc
Cl = Q x ER
ER = Cl / Q
Physiologic Approach
to Cipro Pharmacokinetics
Male with Pneumonia
Given the clearance of ciprofloxacin,
how much drug is required each day
to maintain an average concentration
of 2 mg/L? (peaks of 3-4; troughs ~0.5)
Age:
45 yr
Weight:
80 kg
Drug:
Ciprofloxacin
Serum ciprofloxacin concentrations
average 2 g/mL (mg/L)
Cipro Volume:
1.5 L/kg
Cipro Am’t in body: = 80 x 1.5 x 2
= 240 mg
Cipro Clearance:
= 35 L/hr
= 840 L/day
Male Acute Community
Acquired Pneumonia
Equations
Conc = Dose / V
V = Dose/Conc
Cl = Q x ER
ER = Cl / Q
Physiologic Approach
to Cipro Pharmacokinetics
Male with Pneumonia
Given the clearance of ciprofloxacin,
how much drug is required each day
to maintain an average concentration
of 2 mg/L? (peaks of 3-4; troughs ~0.5)
Age:
45 yr
Weight:
80 kg
Cipro Clearance:
= 840 L/day
Average concentration over a day
2 mg/L
Dose required to maintain [ ]
= 2 (840) mg
= 1680 mg/day
Focus on an Eliminating Organ
How Efficient is a Normal Liver
in removing Theophylline?
Cardiac Output
Proportion of CO to the Liver
Liver Blood Flow
Proportion of Blood as Serum
Liver Serum (plasma) Flow
= 6.0 L/min
= 25%
= 1.5 L/min
= 55%
= 1.5 L/min
Equations
= 0.82 L/min
OR
= 820 mL/min
Conc = Dose / V
V = Dose/Conc Cardiac Output = 85 mL/kg/min 70 kg male
Proportion of Blood as Serum
= 55%
Cl = Q x ER Liver Serum (plasma) Flow
= 85 * 70 * 0.55 * 0.25
ER = Cl / Q
= 818.12 mL/min
Focus on an Eliminating Organ
How Efficient is a Normal Liver
in removing Theophylline?
Cardiac Output
= 6.0 L/min (Blood)
Liver Plasma Flow = 820 mL/min/70 kg male
Theophylline:
Equations
Total clearance
Conc = Dose / V Hepatic Clearance
V = Dose/Conc
Cl = Q x ER
ER = Cl / Q
85% metabolized
15% excreted unchanged
~ 0.7 mL/min/kg
= 50 mL/min (serum)
Cl
H=
Focus on an Eliminating Organ
How Efficient is a Normal Liver
in removing Theophylline?
Cardiac Output
= 6.0 L/min (Blood)
Liver Plasma Flow = 820 mL/min/70 kg male
Theophylline:
Equations
85% metabolized
15% excreted unchanged
~ 0.7 mL/min/kg
= 50 mL/min (serum)
Total clearance
Conc = Dose / V Hepatic Clearance
Cl
V = Dose/Conc
Cl = Q x ER
ER = Cl / Q
Q
BLOOD
H
ER
H=
50(0.85)
= 42.5 mL/min
= 820 mL/min (serum)
=
Focus on an Eliminating Organ
How Efficient is a Normal Liver
in removing Theophylline?
Cardiac Output
= 6.0 L/min (Blood)
Liver Plasma Flow = 820 mL/min/70 kg male
Theophylline:
Equations
85% metabolized
15% excreted unchanged
~ 0.7 mL/min/kg
= 50 mL/min (serum)
Total clearance
Conc = Dose / V Hepatic Clearance
Cl
V = Dose/Conc
Cl = Q x ER
ER = Cl / Q
Q
BLOOD
H
ER
H=
50(0.85)
= 42.5 mL/min
= 820 mL/min (serum)
= 42.5/820 = 0.052
or 5.2%