Distribution
From A Physiologic Perspective
Objectives
•Problems / Questions Related to Introduction
• Distribution From A Physiologic Perspective]
• Five “Distribution Problems” are provided starting
at slide 21. Not all of these problems will be completed in class …
but you are expected to work through them on your own.
Opening Question:
Mr. JR receives 500 mg of Levofloxacin by intravenous bolus
(over 1 minute) and the serum concentration is measured
immediately and found to be 5.0 mg/L.
What is the apparent volume of distribution?
What percent of drug is located in serum?
Distribution
Where does drug go?
Objective
Review Basic Principles related to
drug & chemical / metabolite
distribution in the body
Develop a definition for
Volume of Distribution
Where does the drug go?
Is it confined to blood
or
is it mostly in the blood
or
is it largely confined to tissues?
Facts and Figures
Body Weights
Actual vs Ideal (IBW)
Male: 50 kg + (2.5 kg/inch over 5 ft)
Female: 45.5 kg + (2.3 kg / inch over 5 ft)
Blood Volume (L) ~ 8% of IBW
Body water (L)
~60% of IBW
Barriers to Distribution
1. GI Tract
 Intestinal wall prevents absorption
… not all drugs are absorbed
2. Vascular walls
limits “escape” from serum / blood
3. Cellular walls
limits “free” movement within the body
Plasma or Serum ~ 55%
RBC’s, ~ 45% of whole blood
Extra-cellular
Water
~ 15 L
Intra-cellular Water
~ 25 L
Whole Blood ~ 5 L
Body Water1
Tissue
Skin
Muscle
Brain
Skelton
Adipose
Other
Total
1.
% Water
72
75
75
22
10
%Weight
18
42
2
16
~10
12
100
Skelton, H. Arch Int. Med 1927; 40: 140.
Water
per 70 kg
(L)
9.1
22.1
1.1
2.5
0.7
6.5
42
General Principles of Distribution
1000 mg
10 L
If you add 1000 mg of a drug
to 10 L of water,
what is the final concentration?
Following complete mixing
Concentration (C) = 1000 mg/ 10L
= 100 mg/L
C = Amount / volume
Volume = Amount / C
General Principles of Distribution
1000 mg
If you add 1000 mg of a drug
to 10 L of water,
what is the final concentration?
C = Amount / volume
Volume = Amount / C
10 L
Could the concentration change
as a function of time after addition?
If you knew that you had added
1000 mg of drug and then drew a sample
from a corner of the vessel before
complete mixing occurred,
what would you conclude?
General Principles of Distribution
10 L
Charcoal
Again you add 1000 mg of a drug
1000 mg
to 10 L of water, but now
there is some charcoal in the water
that may bind the drug.
The observed concentration
after complete mixing is 50 mg/L
Since
Volume = Amount / C
then the
apparent volume of distribution is:
= 1000 mg/50 mg/L
= 20L …???
BUT The real volume is 10L
General Principles of Distribution
Again you add 1000 mg of a drug
1000 mg but this time in addition to the charcoal
and 10L of water there is 1 L of oil.
1L
You measure the concentration
in the oil (150 mg/L)
and in the water (25 mg/L).
10 L
Now calculate the volume:
Charcoal
Based on the concentration in the water
Volume = Amount / C
then the
apparent volume of distribution is:
= 1000 mg/25 mg/L
= 40L
General Principles of Distribution
Again you add 1000 mg of a drug
1000 mg but this time in addition to the charcoal
and 10L of water there is 1 L of oil.
1L
You measure the concentration
in the oil (150 mg/L)
and in the water (25 mg/L).
10 L
Now calculate the volume:
Charcoal
Based on the concentration in the oil
Volume = Amount / C
then the
apparent volume of distribution is:
= 1000 mg/150 mg/L
= 6.66 L
General Principles of Distribution
Mass Balance
1000 mg
1L
Water:
Concentration 25 mg/L
True Volume: 10L
Amount of Drug = 250 mg
Apparent Volume = 40L
10 L
Oil:
Charcoal
Concentration 150 mg/L
True Volume: 1L
Amount of Drug = 150 mg
Apparent Volume = 6.66 L
Charcoal:
(therefore)
Amount = 600 mg
General Principles of Distribution
1000 mg
Conclusions
1L
10 L
Charcoal
1. The calculated Apparent Volume
depends on the fluid being
sampled.
2. The volume depends on the host,
and the physical/chemical
properties of the drug or
metabolite
3. The calculated Apparent Volume
rarely reflects a real physiologic
volume.
General Principles of Distribution
1000 mg…so what is the Apparent Volume of
Distribution?
1L
10 L
Charcoal
… it is the volume of sampled fluid
need to account for the total
amount of drug in the body
… at distribution equilibrium …
(following complete mixing).
The volume is not associated with
a particular space or anatomical
area or tissue.
It is a proportionality constant
relating concentration and
amount in the body.
General Principles of Distribution
…so, if it is not real, how useful is it?
1000 mg
Uses:
1L
•
It tells us how much drug must
be added to the body so as to
achieve a specified concentration
in the sampled fluid.
•
In a general way it tells us where
the drug is stored in the body or
where it might be found.
10 L
Charcoal
General Principles of Distribution
L/70 kg
50,000
Quinacrine
20,000
Chloroquine
10,000
5,000
1,000
500
100
50
10
5
Nortriptyline
Digoxin
Propranolol
Quinidine
Quinolones (1- 2 L/kg), Tetracycline
Phenobarbital
Phenytoin
Theophylline (0.45 L/kg)
Aminoglycodises (0.25 L/kg)
ASA
Warfarin
General Principles of Distribution
Question:
If the drug is distributing to total body water,
why are there large differences in the volume
for different drugs?
Physical Chemical properties of the drug
High molecular weight (mabs) and even ICG (MW = 775)
are confined to plasma volume.
Ions (Cl-, Br-) rapidly distribute throughout extra-cellular
fluid but do not easily cross cell membranes.
Other Ions (K+, Ca2+) are actively transported across
membranes. Potassium is predominately intra-cellular.
Protein Binding
General Principles of Distribution
Protein Binding:
Unless a drug is actively transported into cells,
it is generally assumed that only free drug can
distribute to tissues.
In blood, drugs often
bind to albumin.
The unbound (free) drug
can diffuse out of the
blood, into the
extra-cellular water
and often into cells
(intra-cellular water).
Equilibrium is established
General Principles of Distribution
Protein Binding:
Unless a drug is actively transported into cells,
it is generally assumed that only free drug can
distribute to tissues.
The equilibrium
between
Bound & Free
remains in place.
It is also assumed
that at equilibrium
the free concentration
is equal in all tissues
General Principles of Distribution
Protein Binding:
Unless a drug is actively transported into cells,
it is generally assumed that only free drug can
distribute to tissues.
If a drug
is highly bound
within tissues,
the equilibrium
established between
bound and free
will find the majority
of the drug in tissues,
(based on binding
and mass).
General Principles of Distribution
Protein Binding:
Unless a drug is actively transported into cells,
it is generally assumed that only free drug can
distribute to tissues.
Protein binding in
blood will <effectively>
keep drug in blood.
However, since
tissue mass
exceeds blood volume,
any binding in tissues
will shift the equilibrium
toward drug in tissues.
General Principles of Distribution
Protein Binding:
Unless a drug is actively transported into cells,
it is generally assumed that only free drug can
The volume of distribution
distribute to tissues.
of a drug can be viewed as
a relationship between
tissue binding and
binding to protein
within the blood.
If a drug is
highly protein bound
within blood but has
little tissue binding,
the volume of distribution
will be small
(~10L – e.g. warfarin).
General Principles of Distribution
Protein Binding:
Unless a drug is actively transported into cells,
it is generally assumed that only free drug can
distribute to tissues.
Even if a drug is
highly protein bound
within blood but also has
high tissue binding,
the volume of distribution
will be large.
General Principles of Distribution
Protein Binding:
Unless a drug is actively transported into cells,
it is generally assumed that only free drug can
distribute to tissues.
VdTOTAL = VB + VT (fB/fT)
Where VB is blood volume ~ 5L
and VT is body water
(between 30-50 L).
fB and fT is the fraction unbound
in tissue and in blood
The volume of distribution
of a drug can be viewed as
a relationship between
tissue binding and
binding to protein
within the blood.
General Principles of Distribution
Protein Binding:
Unless a drug is actively transported into cells,
it is generally assumed that only free drug can
distribute to tissues.
VdTOTAL = VB + VT (fB/fT)
Where VB is blood volume ~ 5L
and VT is body water
(between 30-50 L).
The volume of distribution
of a drug can be viewed as
a relationship between
If fB is 5% (free in blood or plasma)
tissue binding and
and fT is 100%
binding to protein
(free in issues – no binding)
within the blood.
The final volume
is 5L of blood volume
plus ~2.5L of tissue volume.
7.5L total.
General Principles of Distribution
Protein Binding:
Unless a drug is actively transported into cells,
it is generally assumed that only free drug can
distribute to tissues.
VdTOTAL = VB + VT (fB/fT)
Where VB is blood volume ~ 5L
and VT is body water
(between 30-50 L).
The volume of distribution
of a drug can be viewed as
a relationship between
If fB is 5% (free in blood or plasma)
tissue binding and
But fT is 1%
binding to protein
(free in issues – 99% binding)
within the blood.
The final volume
is 5L of blood volume
plus ~250 L of tissue volume.
255L total.
General Principles of Distribution
Effect of Protein Binding on Volume of Distribution
VdTOTAL = VB + VT (fB/fT)
This makes the
assumption that
the drug may
distribute to all
places in the body
where water exists
and this may not
be true if there is
active transport
in or out
of a particular
tissue.
eg. BBB etc.
General Principles of Distribution
Observe the Effect of Protein Binding
on Volume of Distribution of Propranolol
For propranolol
as the free fraction
increases from
~5% to ~30%
Volume (Vd)
increases from
~125 L to ~800 L.
6-fold increases in
both FF and Vd.
Open circles – Liver disease patients
General Principles of Distribution
L/70 kg
50,000
Quinacrine
20,000
Chloroquine
10,000
5,000
1,000
500
100
50
10
5
Nortriptyline
Digoxin
Five Examples:
Example 5:
Example 2:
Example 1:
Example 4:
Example 3:
Propranolol
Quinidine
Quinolones (1- 2 L/kg), Tetracycline
Phenobarbital
Phenytoin
Theophylline (0.45 L/kg)
Aminoglycodises (0.25 L/kg)
ASA
Warfarin
Cyclosporin … 3000L
Ciprofloxacin … 120L
Levofloxacin … 100L
Levofloxacin … 83.3L
Theophylline … 36L
Notice that the
Volume of distribution
is different
for all drugs and
will also be different
for each patient (levo).
Male Acute Community
Acquired Pneumonia
Distribution Problems
Five Examples:
Example 1: Levofloxacin
Calculate Volume
Example 2:
Example 3:
Example 4:
Example 5:
Ciprofloxacin
Given Volume,
Calculate Concentration
Theophylline
Calculate Volume
…then predict new dose
Levofloxacin
Cyclosporin
General Principles of Distribution
Summary
1. The calculated apparent Volume depends
on the fluid being sampled.
2. Drugs can go anywhere (phys.-chem. prop.)
leaving extra-cellular water to distribute
into bone, fat or … anywhere, any tissue.
3. The apparent Volume depends on the host,
and the physical/chemical properties of the
drug or metabolite.
4. The calculated apparent Volume rarely
reflects a real physiologic volume.
5. The minimum volume* of distribution is
vascular volume (8% IBW: 6’ ♂ = 6.4L).
6. There is no maximum volume*.
First Example:
Levofloxacin
Volume of
Distribution
Blood
Oral
Dose
Liver
GI Tract
IV
Dose
Kidney
Male Acute Community
Acquired Pneumonia
Distribution Problem 1
Calculate Volume
Male with Pneumonia
Age:
45 yr
Weight:
80 kg
Drug:
Levofloxacin
Observe:
Serum levofloxacin
concentration following
i.v. bolus of 500 mg
5 g/mL (mg/L)
Additional Information:
Blood Volume:
8% of body weight
Hematocrit:
0.45
Male Acute Community
Acquired Pneumonia
Distribution Problem 1
Questions
1. What is the Volume of distribution of levo?
2. Where in the body does levo appear
to be located? What percent is located
in the Serum?
3. If the serum levo concentration
is at the mid-point of target…3 g/mL
(a) how much drug is in the serum?
(b) what is the total amount of drug in
your patient (MAC)?
Male Acute Community
Acquired Pneumonia
Equations
Conc = Dose / V
V = Dose/Conc
Distribution Problem 1
Answers.
1. What is the Volume of distribution of
levo?
Dose
=
Initial [ ] =
Levo Volume:
=
2. Proportion in Serum: =
Male Acute Community
Acquired Pneumonia
Equations
Conc = Dose / V
V = Dose/Conc
Distribution Problem 1
Answers.
1. What is the Volume of distribution of levo?
Dose
= 500 mg
Initial [ ] = 5 g/mL (mg/L)
Levo Volume:
= Dose / Conc
= 500 / 5
= 100 L
2. Proportion in Serum: =
Male Acute Community
Acquired Pneumonia
Equations
Conc = Dose / V
V = Dose/Conc
Distribution Problem 1
Answers.
2. Proportion in Serum:
Weight :
80 kg
Levo Volume:
500 mg/ 5 mg/L
Blood Volume:
8% of body weight
Hematocrit:
0.45
Blood volume:
Serum (55%):
Levo Volume:=
=
=
Proportion in Serum: =
Male Acute Community
Acquired Pneumonia
Equations
Conc = Dose / V
V = Dose/Conc
Distribution Problem 1
Answers.
2. Proportion in Serum:
Weight :
80 kg
Levo Volume:
500 mg/ 5 mg/L
Blood Volume:
8% of body weight
Hematocrit:
0.45
Blood volume:
= 0.08 x 80 kg = 6.4 L
Serum (55%):
=6.4 x 0.55 = 3.5 L
Levo Volume: = 500 mg/ 5 mg/L = 100 L
Proportion in Serum: =
Male Acute Community
Acquired Pneumonia
Equations
Conc = Dose / V
V = Dose/Conc
Distribution Problem 1
Answers.
2. Proportion in Serum:
Weight :
80 kg
Levo Volume:
500 mg/ 5 mg/L
Blood Volume:
8% of body weight
Hematocrit:
0.45
Blood volume:
= 0.8 x 80 kg = 6.4 L
Serum (55%):
=6.4 x 0.55 = 3.5 L
Levo Volume: = 500 mg/ 5 mg/L = 100 L
Proportion in Serum:
= 3.5 L/100.0 L
= 3.5%
Male Acute Community
Acquired Pneumonia
Equations
Conc = Dose / V
V = Dose/Conc
Distribution Problem 1
Answers.
3. If the serum levofloxacin concentration
is at the mid-point of target … ~ 3mg/L …
(a) how much drug is in the serum?
(b) what is the total amount of drug in MAC?
Therapeutic Range: 5 - 1 g/mL = mg/L
mid point: 3 mg/L
Amount in body at equilibrium:
=
Amount in serum:
=
Male Acute Community
Acquired Pneumonia
Equations
Conc = Dose / V
V = Dose/Conc
Distribution Problem 1
Answers.
3. If the serum levofloxacin concentration
is at the mid-point of target … ~ 3mg/L …
(a) how much drug is in the serum?
(b) what is the total amount of drug in MAC?
Therapeutic Range: 5 - 1 g/mL = mg/L
mid point: 3 mg/L
Amount in body at equilibrium:
= 3 mg/L x 100.0 L = 300 mg
Amount in serum:
= 3 mg/L x 3.5 L = 10.5 mg
Percent in serum: = 10.5 mg/ 300 mg
= 3.5%
Levofloxacin Distribution Problem 1 Review
Answers.
Volume
100 L
100 L/80kg
= 1.2 L/kg
Recall Levo
monograph
indicated
volume was
between
74 & 112 L.
Body Weight:
Blood Volume:
80 kg
8% of body weight
Serum is 55% of Blood
Serum = (0.08) x (0.55) x (80) = 3.52 L
Serum conc. = 3 g/mL
= 3 mg/L
Amount in Serum:
= (3.5 L) x 3 mg/L)
= 10.5 mg
Amount in Body, based on volume of 100 L
= (3) x (100) = 300 mg
Percent in Serum: 10.5 mg / 300 mg = 3.5%
Second Example: Ciprofloxacin
Volume of
Distribution
Blood
Oral
Dose
Liver
GI Tract
IV
Dose
Kidney
Male Acute Community
Acquired Pneumonia
Distribution Problem 2
This time … given Volume
Male with Pneumonia
Age:
45 yr
Weight:
80 kg
Drug:
Ciprofloxacin
Goal:
Serum ciprofloxacin
concentrations ranging
3 - 4 g/mL (target)
Additional Information:
Cipro Volume:
1.5 L/kg
Blood Volume:
8% of body weight
Hematocrit:
0.45
Male Acute Community
Acquired Pneumonia
Distribution Problem 2
Questions
1. What dose should be given to MAC to
achieve a peak concentration of between
3 and 4 g/mL?
2. What percent is located in the Serum?
3. If the serum cipro concentration
is at the mid-point of target…3.5 g/mL
(a) how much drug is in the serum?
(b) what is the total amount of drug in MAC?
Male Acute Community
Acquired Pneumonia
Equations
Conc = Dose / V
V = Dose/Conc
Distribution Problem 2
Answers.
1. What dose should be given to MAC to
achieve a peak concentration of between
3 and 4 g/mL?
Cipro Volume: 1.5 L/kg
Pt weight:
80 kg
6.4 x 0.55 = 3.5 L
Cipro Volume (L): =
Male Acute Community
Acquired Pneumonia
Equations
Conc = Dose / V
V = Dose/Conc
Distribution Problem 2
Answers.
1. What dose should be given to MAC to
achieve a peak concentration of between
3 and 4 g/mL ?
Cipro Volume: 1.5 L/kg
Pt weight:
80 kg
6.4 x 0.55 = 3.5 L
Cipro Volume (L): = 1.5 L/kg x 80 kg
= 120.0 L
Peak target [ ] mg/L = 3 g/mL
Req. Cipro Dose
=
Male Acute Community
Acquired Pneumonia
Equations
Conc = Dose / V
V = Dose/Conc
Distribution Problem 2
Answers.
1. What dose should be given to MAC to
achieve a peak concentration of between
3 and 4 g/mL?
Cipro Volume: 1.5 L/kg
Pt weight:
80 kg
6.4 x 0.55 = 3.5 L
Cipro Volume (L): = 1.5 L/kg x 80 kg
= 120.0 L
Peak target [ ] mg/L = 3 g/mL (mg/L)
Req. Cipro Dose
= 3 mg/L x 120 L
= 360 mg
Male Acute Community
Acquired Pneumonia
Equations
Conc = Dose / V
V = Dose/Conc
Distribution Problem 2
Answers.
1. What dose should be given to MAC to
achieve a peak concentration of between
3 and 4 g/mL?
Cipro Volume: 1.5 L/kg
Pt weight:
80 kg
6.4 x 0.55 = 3.5 L
Cipro Volume (L): = 1.5 L/kg x 80 kg
= 120.0 L
Peak target [ ] mg/L = 4 g/mL (mg/L)
Req. Cipro Dose
= 4 mg/L x 120 L
= 480 mg
Male Acute Community
Acquired Pneumonia
Equations
Conc = Dose / V
V = Dose/Conc
Distribution Problem 2
Answers.
1. What dose should be given to MAC to
achieve a peak concentration of between
3 and 4 g/mL?
Peak target 3 mg/L = Dose = 360mg
Peak target 4 mg/L = Dose = 480mg
Common dose of Cipro IV?
Male Acute Community
Acquired Pneumonia
Equations
Conc = Dose / V
V = Dose/Conc
Distribution Problem 2
Answers.
1. What dose should be given to MAC to
achieve a peak concentration of between
3 and 4 g/mL?
Peak target 3 mg/L = Dose = 360mg
Peak target 4 mg/L = Dose = 480mg
Common dose of Cipro IV?
400 mg
Male Acute Community
Acquired Pneumonia
Equations
Conc = Dose / V
V = Dose/Conc
Distribution Problem 2
Answers.
2. What percent is located in the Serum?
Weight :
80 kg
Cipro Volume: 1.5 L/kg
Blood Volume:
8% of body weight
Hematocrit:
0.45
Blood volume:
Serum vol. (55%):
Cipro Volume:
0.8 x 80 kg = 6.4 L
6.4 x 0.55 = 3.5 L
1.75 L/kg x 80 kg
140.0 L
Proportion in Serum: 3.5 L/140.0 L = 2.5%
Male Acute Community
Acquired Pneumonia
Equations
Conc = Dose / V
V = Dose/Conc
Distribution Problem 2
Answers.
2. What percent is located in the Serum?
Weight :
80 kg
Cipro Volume: 1.5 L/kg
Blood Volume:
8% of body weight
Hematocrit:
0.45
Blood volume:
Serum vol. (55%):
Cipro Volume:
0.08 x 80 kg = 6.4 L
6.4 x 0.55 = 3.5 L
1.5 L/kg x 80 kg
120.0 L
Proportion in Serum: 3.5 L/120.0 L = 2.9%
Ciprofloxacin Distribution Problem 2 Review
Answers.
Body Weight:
Blood Volume:
80 kg
8% of body weight
Serum is 55% of Blood
Serum = (0.08) x (0.55) x (80) = 3.52 L
Volume
1.5 L/kg
120.0 L
Serum conc. = 3 g/mL
= 3 mg/L
Amount in Serum:
= (3.5 L) x 3 mg/L)
= 10.5 mg
Amount in Body, based on volume of 120 L
= (3) x (120) = 360 mg
(Dose = 400 mg)
Percent in Serum: 10.5 mg / 360 mg = 2.9%
Third Example:
Theophylline
Volume of
Distribution
Blood
Oral
Dose
Liver
GI Tract
IV
Dose
Kidney
Severe Asthmatic Male
Distribution Problem 3
Male Asthmatic
Age:
45 yr
Weight:
80 kg
Drug:
Theophylline
Goal:
Serum theophylline
in the therapeutic range
10 – 20 g/mL
Additional Information:
Initial Theophylline Dose of 300 mg
produces a peak following a bolus
iv dose of 8.33 mg/L.
Severe Asthmatic Male
Distribution Problem 3
Questions
1. What is the volume of distribution
of theophylline?
2. What percent is located in the Serum?
3. If we need to produce a peak serum
theophylline concentration near the
mid-point of target… (~15 mg/L),
what should the dose be?
Severe Asthmatic Male
Equations
Conc = Dose / V
V = Dose/Conc
Distribution Problem 3
Answers.
1. What is the volume of distribution
of theophylline?
Theophylline Dose = 300 mg
Peak [ ] mg/L
= 8.33 mg/L.
0.55 = 3.5 L
Theophylline Volume:
=
Vol. Expressed as L/kg:
=
Severe Asthmatic Male
Equations
Conc = Dose / V
V = Dose/Conc
Distribution Problem 3
Answers.
1. What is the volume of distribution
of theophylline?
Theophylline Dose = 300 mg
Peak [ ] mg/L
= 8.33 mg/L.
0.55 = 3.5 L
Theophylline Volume: = 300 mg / 8.33 mg/L
= 36 L
Expressed as L/kg:
= 36 L / 80 kg
= 0.45 L/kg
Severe Asthmatic Male
Equations
Conc = Dose / V
V = Dose/Conc
Distribution Problem 3
Answers.
2. Proportion in Serum?
Weight :
80 kg
Theophylline Volume: 0.45 L/kg
Blood Volume:
8% of body weight
Hematocrit:
0.45
Blood volume:
0.8 x 80 kg = 6.4 L
Serum (55%):
6.4 x 0.55 = 3.5 L
Theophylline Volume:
0.45 L/kg x 80 kg
36.0 L
Proportion in Serum: 3.5 L / 36.0 L = 9.8%
Severe Asthmatic Male
Equations
Conc = Dose / V
V = Dose/Conc
Distribution Problem 3
Answers.
2. Proportion in Serum?
Weight :
80 kg
Theophylline Volume: 0.45 L/kg
Blood Volume:
8% of body weight
Hematocrit:
0.45
Blood volume:
0.08 x 80 kg = 6.4 L
Serum (55%):
6.4 x 0.55 = 3.5 L
Theophylline Volume:
= 0.45 L/kg x 80 kg
= 36.0 L
Proportion in Serum:
= 3.5 L / 36.0 L
= 9.8%
Severe Asthmatic Male
Equations
Conc = Dose / V
V = Dose/Conc
Distribution Problem 3
Answers.
3. If we need to produce a peak serum
theophylline concentration near the
mid-point of target… (~15 mg/L),
what should the dose be?
Therapeutic Range: 10 – 20 g/mL = mg/L
mid point: 15 mg/L
Amount in body at 15 mg/L:
15 mg/L x 36.0 L = 540 mg
Dose:
15 mg/L x 3.5 L = 52.5 mg
Severe Asthmatic Male
Equations
Conc = Dose / V
V = Dose/Conc
Distribution Problem 3
Answers.
3. If we need to produce a peak serum
theophylline concentration near the
mid-point of target… (~15 mg/L),
what should the dose be?
Therapeutic Range: 10 – 20 g/mL = mg/L
mid point: 15 mg/L
Amount in body at 15 mg/L:
15 mg/L x 36.0 L = 540 mg
Dose: actual dose???
540 mg
peak of 15 mg/L
Severe Asthmatic Male
Equations
Conc = Dose / V
V = Dose/Conc
Distribution Problem 3
Answers.
3. If we need to produce a peak serum
theophylline concentration near the
mid-point of target… (~15 mg/L),
what should the dose be?
Dose: actual dose???
540 mg
= peak of 15 mg/L
600 mg
= peak conc?
= 600 mg / 36 L
= 16.6 mg/L
500 mg
= peak conc?
= 500 mg / 36 L
= 13.9 mg/L
Distribution Problem 3
Answers.
Body Weight:
Blood Volume:
80 kg
8% of body weight
Serum is 55% of Blood
Serum = (0.08) x (0.55) x (80) = 3.52 L
Volume
0.45 L/kg
36.0 L
Serum conc. = 15 g/mL
= 15 mg/L
Amount in Serum:
= (3.5 L) x 15 mg/L)
= 52.5 mg
Amount in Body, based on volume of 36 L
= (15) x (36) = 540 mg
Percent in Serum: 52.5 mg / 540 mg = 9.8%
Fourth Example: Levofloxacin in a different patient
Volume of
Distribution
Blood
Oral
Dose
Liver
GI Tract
IV
Dose
Kidney
Distribution Question
Example 4
Mr. JR, as 45 yr old male
weighing 80 kg and
appears to have Community
Acquired Pneumonia. He is
prescribed 500 mg of levofloxacin,
once per day for 7 days.
Immediately following the first
dose, given by I.V. bolus, a plasma
concentration is measured as 6.0 mg/L.
1. Calculate the apparent volume of distribution.
2. What percent of the drug is in plasma?
3. Other Questions about “Distribution”?
Distribution Question
Example 4
Equations
Conc = Dose / V
V = Dose/Conc
Mr. JR, receives 500 mg
and the initial plasma
concentration is measured as 6.0 mg/L.
1. Calculate the apparent
volume of distribution.
Conc
= Dose / Volume
Volume = Dose / Conc
= 500 mg / 6.0 mg/L
=
Distribution Question
Example 4
Equations
Conc = Dose / V
V = Dose/Conc
Mr. JR, receives 500 mg
and the initial plasma
concentration is measured as 6.0 mg/L.
1. Calculate the apparent
volume of distribution.
Conc
= Dose / Volume
Volume = Dose / Conc
= 500 mg / 6.0 mg/L
= 83.33 liters
Notice that this volume is slightly different
than the 100 L calculated for a different patient
Expressed per kg of body weight
=
Distribution Question
Example 4
Equations
Conc = Dose / V
V = Dose/Conc
Mr. JR, receives 500 mg
and the initial plasma
concentration is measured as 6.0 mg/L.
1. Calculate the apparent
volume of distribution.
Conc
= Dose / Volume
Volume = Dose / Conc
= 500 mg / 6.0 mg/L
= 83.33 liters
Expressed per kg of body weight
= 83.33 liters / 80 kg
=1.04 L/kg
Distribution Question
Example 4
Equations
Conc = Dose / V
V = Dose/Conc
Mr. JR, receives 500 mg
and the initial plasma
concentration is measured as 6.0 mg/L.
1. Calculate the apparent volume of distribution.
Volume = 83.33 liters
Vol per kg of body weight = 1.04 L/kg
2. What percent of the drug is in plasma?
Blood is ~8% of body weight
Mr. JR weighs 80 kg.
Blood Volume is ~ 6.4 L
Plasma volume is ~55% of blood volume.
Plasma volume = 6.4 L x 0.55 = 3.52 L.
Distribution Question
Example 4
Equations
Mr. JR, receives 500 mg
and the initial plasma
concentration is measured as 6.0 mg/L.
Conc = Dose / V
2. What percent of the drug is in plasma?
V = Dose/Conc
Plasma volume = 6.4 L x 0.55 = 3.52 L.
Conc in plasma = 6.0 mg/L
Amount in plasma =
Distribution Question
Example 4
Equations
Conc = Dose / V
V = Dose/Conc
Mr. JR, receives 500 mg
and the initial plasma
concentration is measured as 6.0 mg/L.
2. What percent of the drug is in plasma?
Plasma volume = 6.4 L x 0.55 = 3.52 L.
Conc in plasma = 6.0 mg/L
Amount in plasma = 3.52 L x 6.0 mg/L
= 21.12 mg.
How much is in the body?
volume distrib. = 83.33 L
Conc in plasma = 6.0 mg/L
Amount in body =
Distribution Question
Example 4
Equations
Conc = Dose / V
V = Dose/Conc
Mr. JR, receives 500 mg
and the initial plasma
concentration is measured as 6.0 mg/L.
2. What percent of the drug is in plasma?
Plasma volume = 6.4 L x 0.55 = 3.52 L.
Conc in plasma = 6.0 mg/L
Amount in plasma = 3.52 L x 6.0 mg/L
= 21.12 mg.
How much is in the body?
volume distrib. = 83.33 L
Conc in plasma = 6.0 mg/L
Amount in body
= 6.0 mg/L x 83.33L
= 500 mg (dose)
Distribution Question
Example 4
Equations
Conc = Dose / V
V = Dose/Conc
Mr. JR, receives 500 mg
and the initial plasma
concentration is measured as 6.0 mg/L.
2. What percent of the drug is in plasma?
Amount in plasma
= 3.52 L x 6.0 mg/L
= 21.12 mg.
Amount in body = 6.0 mg/L x 83.33L
= 500 mg (dose)
Proportion in plasma ?
=
Distribution Question
Example 4
Equations
Conc = Dose / V
V = Dose/Conc
Mr. JR, receives 500 mg
and the initial plasma
concentration is measured as 6.0 mg/L.
2. What percent of the drug is in plasma?
Amount in plasma
= 3.52 L x 6.0 mg/L
= 21.12 mg.
Amount in body = 6.0 mg/L x 83.33L
= 500 mg (dose)
Proportion in plasma
= 21.12 mg / 500 mg
= 0.042
= 4.2%
Fifth Example:
Cyclosporin
Volume of
Distribution
Blood
Oral
Dose
Liver
GI Tract
IV
Dose
Kidney
A Fifth Example - cyclosporin
Cyclosporin (CsA), 600 mg is
administered to a female transplant
patient – MJ, who weighs 55 kg, by IV
bolus. Cyclosporin is “highly bound to
RBC” and the “Blood : Plasma ratio is 2”.
Immediately after the dose a blood
sample is taken and the blood concentration
is measured as 200 ng/mL.
(a) What is the apparent volume of distrib?
(b) What percent of CsA in the body is
located in blood / plasma in this patient?
A Fifth Example - cyclosporin
Equations
Conc = Dose / V
V = Dose/Conc
Cyclosporin (CsA), 600 mg is
administered to a female transplant
patient – MJ, who weighs 55 kg, by IV
bolus. Cyclosporin is “highly bound to
RBC” and the “Blood : Plasma ratio is 2”.
Immediately after the dose a blood
sample is taken and the blood concentration
is measured as 200 ng/mL. (200 ug/L)
(a) What is the apparent volume of distrib?
Conc
= Dose / Volume
Volume = Dose / Conc
=
A Fifth Example - cyclosporin
Equations
Conc = Dose / V
V = Dose/Conc
Cyclosporin (CsA), 600 mg is
administered to a female transplant
patient – MJ, who weighs 55 kg, by IV
bolus. Cyclosporin is “highly bound to
RBC” and the “Blood : Plasma ratio is 2”.
Immediately after the dose a blood
sample is taken and the blood concentration
is measured as 200 ng/mL. (200 ug/L)
(a) What is the apparent volume of distrib?
Conc
= Dose / Volume
Volume = Dose / Conc
= 600 mg / 200.0 ug/L
= 600 mg / 0.2 mg/L
= 3,000 liters
A Fifth Example - cyclosporin
Equations
Conc = Dose / V
V = Dose/Conc
Cyclosporin (CsA), 600 mg is
administered to a female transplant
patient – MJ, who weighs 55 kg, by IV
bolus. Cyclosporin is “highly bound to
RBC” and the “Blood : Plasma ratio is 2”.
If, immediately after the dose a blood
sample is taken and the plasma concentration
is measured as 100 ng/mL. (100 ug/L)
(a) What is the apparent volume of distrib?
Conc
= Dose / Volume
Volume = Dose / Conc
=
A Fifth Example - cyclosporin
Equations
Conc = Dose / V
V = Dose/Conc
Cyclosporin (CsA), 600 mg is
administered to a female transplant
patient – MJ, who weighs 55 kg, by IV
bolus. Cyclosporin is “highly bound to
RBC” and the “Blood : Plasma ratio is 2”.
If, immediately after the dose a blood
sample is taken and the plasma concentration
is measured as 100 ng/mL. (100 ug/L)
(a) What is the apparent volume of distrib?
Conc
= Dose / Volume
Volume = Dose / Conc
= 600 mg / 100.0 ug/L
= 600 mg / 0.1 mg/L
= 6,000 liters
A Fifth Example - cyclosporin
Equations
Conc = Dose / V
V = Dose/Conc
Cyclosporin (CsA), 600 mg is
administered to a female transplant
patient – MJ, who weighs 55 kg, by IV
bolus. Cyclosporin is “highly bound to
RBC” and the “Blood : Plasma ratio is 2”.
Immediately after the dose a blood
sample is taken and the blood concentration
Is measured as 200 ng/mL.
(a) What is the apparent volume of distrib?
(b) What percent of CsA in the body is
located in whole blood in this patient?
Blood is ~8% of body weight
Ms. MJ weighs 55 kg.
MJ’s hematocrit is 0.45 (45% cells)
Blood Volume
=
A Fifth Example - cyclosporin
Equations
Conc = Dose / V
V = Dose/Conc
Cyclosporin (CsA), 600 mg is
administered to a female transplant
patient – MJ, who weighs 55 kg, by IV
bolus. Cyclosporin is “highly bound to
RBC” and the “Blood : Plasma ratio is 2”.
Immediately after the dose a blood
sample is taken and the blood concentration
Is measured as 200 ng/mL.
(a) What is the apparent volume of distrib?
(b) What percent of CsA in the body is
located in whole blood in this patient?
Blood is ~8% of body weight
Ms. MJ weighs 55 kg.
MJ’s hematocrit is 0.45 (45% cells)
Blood Volume
= 55 kg x 0.08
= 4.4 L
A Fifth Example - cyclosporin
Equations
Conc = Dose / V
V = Dose/Conc
Cyclosporin (CsA), 600 mg is
administered to a female transplant
patient – MJ, who weighs 55 kg, by IV
bolus. Cyclosporin is “highly bound to
RBC” and the “Blood : Plasma ratio is 2”.
Immediately after the dose a blood
sample is taken and the blood concentration
Is measured as 200 ng/mL.
(b) What percent of CsA in the body is
located in whole blood in this patient?
Blood Volume
= 4.4 L
How much is in Blood?
=
A Fifth Example - cyclosporin
Equations
Conc = Dose / V
V = Dose/Conc
Cyclosporin (CsA), 600 mg is
administered to a female transplant
patient – MJ, who weighs 55 kg, by IV
bolus. Cyclosporin is “highly bound to
RBC” and the “Blood : Plasma ratio is 2”.
Immediately after the dose a blood
sample is taken and the blood concentration
Is measured as 200 ng/mL.
(a) What percent of CsA in the body is
located in whole blood in this patient?
Blood Volume
= 4.4 L
How much is in Blood?
= 4.4 L x 0.2 mg/L
= 0.88 mg
How much is in the body?
Amount in body =
A Fifth Example - cyclosporin
Equations
Conc = Dose / V
V = Dose/Conc
Cyclosporin (CsA), 600 mg is
administered to a female transplant
patient – MJ, who weighs 55 kg, by IV
bolus. Blood sample measures 200 ng/mL.
(b) What percent of CsA in the body is
located in whole blood in this patient?
Blood Volume
= 4.4 L
How much is in Blood?
= 4.4 L x 0.2 mg/L
= 0.88 mg
How much is in the body?
Amount in body = 0.2 mg/L x 3000L
= 600 mg (dose)
Proportion in whole blood ?
A Fifth Example - cyclosporin
Equations
Conc = Dose / V
V = Dose/Conc
Cyclosporin (CsA), 600 mg is
administered to a female transplant
patient – MJ, who weighs 55 kg, by IV
bolus. Blood sample measures 200 ng/mL.
(a) What percent of CsA in the body is
located in whole blood in this patient?
How much is in Blood?
= 0.88 mg
How much is in the body?
= 600 mg (dose)
Proportion in whole blood ?
= 0.88 mg / 600 mg
= 0.0015
= 0.15%
A Fifth Example - cyclosporin
Equations
Conc = Dose / V
V = Dose/Conc
Cyclosporin (CsA), 600 mg is
administered to a female transplant
patient – MJ, who weighs 55 kg, by IV
bolus. Cyclosporin is “highly bound to
RBC” and the “Blood : Plasma ratio is 2”.
Immediately after the dose a blood
sample is taken and the plasma concentration
is measured as 100 ng/mL.
(b) What percent of CsA in the body is
located in plasma in this patient?
Plasma Volume = 4.4 L x 0.55 = 2.42 L
How much is in plasma?
=
A Fifth Example - cyclosporin
Equations
Conc = Dose / V
V = Dose/Conc
Cyclosporin (CsA), 600 mg is
administered to a female transplant
patient – MJ, who weighs 55 kg, by IV
bolus. Cyclosporin is “highly bound to
RBC” and the “Blood : Plasma ratio is 2”.
Immediately after the dose a blood
sample is taken and the plasma concentration
is measured as 100 ng/mL.
(a) What percent of CsA in the body is
located in plasma in this patient?
Plasma Volume = 2.42 L
How much is in Plasma?
= 2.42 L x 0.1 mg/L
= 0.242 mg
How much is in the body?
Amount in body =
A Fifth Example - cyclosporin
Equations
Conc = Dose / V
V = Dose/Conc
Cyclosporin (CsA), 600 mg is
administered to a female transplant
patient – MJ, who weighs 55 kg, by IV
bolus. Plasma sample measures 100 ng/mL.
(b) What percent of CsA in the body is
located in whole plasma in this patient?
Plasma Volume = 2.42 L
How much is in Plasma?
= 2.42 L x 0.1 mg/L
= 0.242 mg
How much is in the body?
Amount in body = 0.1 mg/L x 6000L
= 600 mg (dose)
Proportion in Plasma ?
A Fifth Example - cyclosporin
Equations
Conc = Dose / V
V = Dose/Conc
Cyclosporin (CsA), 600 mg is
administered to a female transplant
patient – MJ, who weighs 55 kg, by IV
bolus. Plasma sample measures 100 ng/mL.
(a) What percent of CsA in the body is
located in plasma in this patient?
How much is in Plasma?
= 0.242 mg
How much is in the body?
= 600 mg (dose)
Proportion in plasma ?
= 0.242 mg / 600 mg
= 0.000403
= 0.0403%
~ 0.88 mg
A Fifth Example - cyclosporin
Comparison
Concentration (ng/mL)
Tissue Volume (L)
Amount in Tissue (mg)
App Vol. Dist. (L)
Dose (mg)
Percent in blood/plasma (%)
Blood
: Plasma
200
4.4
0.88
3,000
600
0.15
100
2.42
0.242
6,000
600
0.04
Does the difference in apparent volumes imply
anything about where cyclosporin distributes to?
If you are told*(published knowledge) that a
particular concentration must be achieved
in this patient; e.g. 400 ng/mL in whole blood …
What volume of distribution would you use?
What is your recommended dose?
~ 0.88 mg
A Fifth Example - cyclosporin
Comparison
Concentration (ng/mL)
Tissue Volume (L)
Amount in Tissue (mg)
App Vol. Dist. (L)
Dose (mg)
Percent in blood/plasma (%)
Blood
: Plasma
200
4.4
0.88
3,000
600
0.15
100
2.42
0.242
6,000
600
0.04
Does the difference in apparent volumes imply
anything about where cyclosporin distributes to?
If you are told*(published knowledge: ~ MIC, ED50, therap range)
that a particular concentration must be achieved
in this patient; e.g. 400 ng/mL in whole blood …
What volume of distribution would you use? (VolBLOOD)
What is your recommended dose? (1.2 gm)
General Principles of Distribution
Summary
1. The calculated apparent Volume depends
on the fluid being sampled.
2. Drugs can go anywhere (phys.-chem. prop.)
leaving extra-cellular water to distribute
into bone, fat or … anywhere, any tissue.
3. The apparent Volume depends on the host,
and the physical/chemical properties of the
drug or metabolite.
4. The calculated apparent Volume rarely
reflects a real physiologic volume.
5. The minimum volume* of distribution is
vascular volume (8% IBW: 6’ ♂ = 6.4L).
6. There is no maximum volume*.6