DistributionFrom A Physiologic Perspective

•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.

Objectives

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?

ObjectiveReview Basic Principles related to

drug & chemical / metabolite distribution in the body

Develop a definition forVolume of Distribution

Where does the drug go?

Is it confined to bloodor

is it mostly in the blood or

is it largely confined to tissues?

Facts and Figures

Body WeightsActual 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 IBWBody water (L)~60% of IBW

Barriers to Distribution1. GI Tract

Intestinal wall prevents absorption… not all drugs are absorbed

2. Vascular wallslimits “escape” from serum / blood

3. Cellular walls limits “free” movement within the body

Extra-cellularWater~ 15 L

Intra-cellular Water~ 25 L

RBC’s, ~ 45% of whole bloodPlasma or Serum ~ 55%

Whole Blood ~ 5 L

Body Water1

1. Skelton, H. Arch Int. Med 1927; 40: 140.

Tissue % Water %Weight Waterper 70 kg ( L )

Skin 72 18 9.1Muscle 75 42 22.1Brain 75 2 1.1Skelton 22 16 2.5Adipose 10 ~10 0.7Other 12 6.5Total 100 42

General Principles of Distribution

10 L

1000 mg If you add 1000 mg of a drug to 10 L of water,

what is the final concentration?

Following complete mixingConcentration (C) = 1000 mg/ 10L= 100 mg/L

C = Amount / volumeVolume = Amount / C

General Principles of Distribution

10 L

1000 mgIf you add 1000 mg of a drug

to 10 L of water, what is the final concentration?

Could the concentration change as a function of time after addition?

C = Amount / volumeVolume = Amount / C

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

1000 mgAgain you add 1000 mg of a drug

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

SinceVolume = Amount / C

then the apparent volume of distribution is:

= 1000 mg/50 mg/L= 20L …???

BUT The real volume is 10L

Charcoal

General Principles of Distribution

10 L

1000 mgAgain you add 1000 mg of a drug

but this time in addition to the charcoal and 10L of water there is 1 L of oil.

You measure the concentration in the oil (150 mg/L)

and in the water (25 mg/L).

Now calculate the volume:

Based on the concentration in the waterVolume = Amount / C

then the apparent volume of distribution is:

= 1000 mg/25 mg/L= 40L

Charcoal

1L

Again you add 1000 mg of a drug but this time in addition to the charcoal

and 10L of water there is 1 L of oil.

You measure the concentration in the oil (150 mg/L)

and in the water (25 mg/L).

General Principles of Distribution

10 L

1000 mg

Now calculate the volume:

Based on the concentration in the oilVolume = Amount / C

then the apparent volume of distribution is:

= 1000 mg/150 mg/L= 6.66 L

Charcoal

1L

Mass Balance

Water:Concentration 25 mg/L

True Volume: 10LAmount of Drug = 250 mgApparent Volume = 40L

Oil:Concentration 150 mg/L

True Volume: 1LAmount of Drug = 150 mgApparent Volume = 6.66 L

Charcoal: (therefore)Amount = 600 mg

General Principles of Distribution

10 L

1000 mg

Charcoal

1L

Conclusions

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

10 L

1000 mg

Charcoal

1L

…so what is the Apparent Volume of Distribution?

… 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

10 L

1000 mg

Charcoal

1L

…so, if it is not real, how useful is it?

Uses:

• 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.

General Principles of Distribution

10 L

1000 mg

Charcoal

1L

L/70 kg50,000

20,000

10,000

5,000

1,000

500

100

50

10

5

General Principles of Distribution

Quinacrine

Chloroquine

NortriptylineDigoxin

PropranololQuinidineQuinolones (1- 2 L/kg), TetracyclinePhenobarbitalPhenytoinTheophylline (0.45 L/kg)Aminoglycodises (0.25 L/kg)ASAWarfarin

Question:If the drug is distributing to total body water, why are there large differences in the volume for different drugs?

General Principles of Distribution

Physical Chemical properties of the drugHigh 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

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 betweenbound 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 distribute to tissues. The volume of distribution

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.

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

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

Protein Binding:Unless a drug is actively transported into cells, it is generally assumed that only free drug can distribute to tissues.

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

VdTOTAL = VB + VT (fB/fT)

Where VB is blood volume ~ 5L and VT is body water (between 30-50 L).

If fB is 5% (free in blood or plasma)and fT is 100%

(free in issues – no binding)The final volume

is 5L of blood volume plus ~2.5L of tissue volume.

7.5L total.

Protein Binding:Unless a drug is actively transported into cells, it is generally assumed that only free drug can distribute to tissues.

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

VdTOTAL = VB + VT (fB/fT)

Where VB is blood volume ~ 5L and VT is body water (between 30-50 L).

If fB is 5% (free in blood or plasma)But fT is 1%

(free in issues – 99% binding)The final volume

is 5L of blood volume plus ~250 L of tissue volume.

255L total.

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.

Effect of Protein Binding on Volume of Distribution

General Principles of Distribution

Observe the Effect of Protein Binding on Volume of Distribution of Propranolol

For propranololas 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 kg50,000

20,000

10,000

5,000

1,000

500

100

50

10

5

General Principles of Distribution

Quinacrine

Chloroquine

NortriptylineDigoxin

PropranololQuinidineQuinolones (1- 2 L/kg), TetracyclinePhenobarbitalPhenytoinTheophylline (0.45 L/kg)Aminoglycodises (0.25 L/kg)ASAWarfarin

Five Examples:Example 5: Cyclosporin … 3000L Example 2: Ciprofloxacin … 120LExample 1: Levofloxacin … 100LExample 4: Levofloxacin … 83.3LExample 3: Theophylline … 36L

Notice that the

Volume of distributionis different

for all drugs and will also be different

for each patient (levo).

Distribution ProblemsFive Examples:Example 1: Levofloxacin

Calculate Volume

Example 2: CiprofloxacinGiven Volume, Calculate Concentration

Example 3: TheophyllineCalculate Volume…then predict new dose

Example 4: Levofloxacin Example 5: Cyclosporin

Male Acute Community Acquired Pneumonia

General Principles of Distribution

Summary1. 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*.

Volume of Distribution

Blood

Liver

Kidney

GI TractOralDose

IVDose

First Example: Levofloxacin

Distribution Problem 1Calculate Volume

Male with PneumoniaAge: 45 yrWeight: 80 kgDrug: Levofloxacin

Observe: Serum levofloxacin concentration followingi.v. bolus of 500 mg

5 g/mL (mg/L)

Additional Information:Blood Volume: 8% of body weightHematocrit: 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

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 mgInitial [ ] = 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 kgLevo Volume: 500 mg/ 5 mg/L Blood Volume: 8% of body weightHematocrit: 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 kgLevo Volume: 500 mg/ 5 mg/L Blood Volume: 8% of body weightHematocrit: 0.45

Blood volume: = 0.08 x 80 kg = 6.4 LSerum (55%): =6.4 x 0.55 = 3.5 LLevo 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 kgLevo Volume: 500 mg/ 5 mg/L Blood Volume: 8% of body weightHematocrit: 0.45

Blood volume: = 0.8 x 80 kg = 6.4 LSerum (55%): =6.4 x 0.55 = 3.5 LLevo 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/Lmid 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/Lmid 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%

Male Acute Community Acquired Pneumonia

Equations

Conc = Dose / V

V = Dose/Conc

Levofloxacin Distribution Problem 1 Review

Answers.Body Weight: 80 kgBlood Volume: 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%

Volume100 L

100 L/80kg= 1.2 L/kg

Recall Levo monograph

indicated volume was

between 74 & 112 L.

Volume of Distribution

Blood

Liver

Kidney

GI TractOralDose

IVDose

Second Example: Ciprofloxacin

Distribution Problem 2This time … given Volume

Male with PneumoniaAge: 45 yrWeight: 80 kgDrug: Ciprofloxacin

Goal: Serum ciprofloxacin concentrations ranging

3 - 4 g/mL (target)

Additional Information:Cipro Volume: 1.5 L/kgBlood Volume: 8% of body weightHematocrit: 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

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/kgPt weight: 80 kg6.4 x 0.55 = 3.5 LCipro 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/kgPt weight: 80 kg6.4 x 0.55 = 3.5 LCipro Volume (L): = 1.5 L/kg x 80 kg

= 120.0 L

Peak target [ ] mg/L = 3 g/mLReq. 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/kgPt weight: 80 kg6.4 x 0.55 = 3.5 LCipro 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/kgPt weight: 80 kg6.4 x 0.55 = 3.5 LCipro 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 kgCipro Volume: 1.5 L/kgBlood Volume: 8% of body weightHematocrit: 0.45

Blood volume: 0.8 x 80 kg = 6.4 LSerum vol. (55%): 6.4 x 0.55 = 3.5 LCipro Volume: 1.75 L/kg x 80 kg

140.0 LProportion 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 kgCipro Volume: 1.5 L/kgBlood Volume: 8% of body weightHematocrit: 0.45

Blood volume: 0.08 x 80 kg = 6.4 LSerum vol. (55%): 6.4 x 0.55 = 3.5 LCipro Volume: 1.5 L/kg x 80 kg

120.0 LProportion in Serum: 3.5 L/120.0 L = 2.9%

Male Acute Community Acquired Pneumonia

Equations

Conc = Dose / V

V = Dose/Conc

Ciprofloxacin Distribution Problem 2 ReviewAnswers.Body Weight: 80 kgBlood Volume: 8% of body weight

Serum is 55% of BloodSerum = (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 120 L= (3) x (120) = 360 mg

(Dose = 400 mg)

Percent in Serum: 10.5 mg / 360 mg = 2.9%

Volume1.5 L/kg

120.0 L

Volume of Distribution

Blood

Liver

Kidney

GI TractOralDose

IVDose

Third Example: Theophylline

Distribution Problem 3

Male AsthmaticAge: 45 yrWeight: 80 kgDrug: 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 distributionof 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

Distribution Problem 3

Answers.

1. What is the volume of distributionof theophylline?

Theophylline Dose = 300 mg Peak [ ] mg/L = 8.33 mg/L.0.55 = 3.5 LTheophylline 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 distributionof theophylline?

Theophylline Dose = 300 mg Peak [ ] mg/L = 8.33 mg/L.0.55 = 3.5 LTheophylline Volume: = 300 mg / 8.33 mg/L

= 36 LExpressed 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 kgTheophylline Volume: 0.45 L/kgBlood Volume: 8% of body weightHematocrit: 0.45

Blood volume: 0.8 x 80 kg = 6.4 LSerum (55%): 6.4 x 0.55 = 3.5 LTheophylline Volume: 0.45 L/kg x 80 kg

36.0 LProportion 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 kgTheophylline Volume: 0.45 L/kgBlood Volume: 8% of body weightHematocrit: 0.45

Blood volume: 0.08 x 80 kg = 6.4 LSerum (55%): 6.4 x 0.55 = 3.5 LTheophylline Volume: = 0.45 L/kg x 80 kg

= 36.0 LProportion 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/Lmid 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/Lmid 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/L600 mg = peak conc?

= 600 mg / 36 L= 16.6 mg/L

500 mg = peak conc?= 500 mg / 36 L= 13.9 mg/L

Severe Asthmatic Male

Equations

Conc = Dose / V

V = Dose/Conc

Distribution Problem 3

Answers.Body Weight: 80 kgBlood Volume: 8% of body weight

Serum is 55% of Blood

Serum = (0.08) x (0.55) x (80) = 3.52 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%

Volume0.45 L/kg

36.0 L

Volume of Distribution

Blood

Liver

Kidney

GI TractOralDose

IVDose

Fourth Example: Levofloxacin in a different patient

Distribution QuestionExample 4

Mr. JR, as 45 yr old male weighing 80 kg and

appears to have CommunityAcquired 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 QuestionExample 4

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 / VolumeVolume = Dose / Conc

= 500 mg / 6.0 mg/L=

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 / VolumeVolume = Dose / Conc

= 500 mg / 6.0 mg/L= 83.33 liters

Expressed per kg of body weight=

Equations

Conc = Dose / V

V = Dose/Conc

Notice that this volume is slightly different than the 100 L calculated for a different patient

Distribution QuestionExample 4

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 / VolumeVolume = 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

Equations

Conc = Dose / V

V = Dose/Conc

Distribution QuestionExample 4

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 weightMr. JR weighs 80 kg. Blood Volume is ~ 6.4 LPlasma volume is ~55% of blood volume.Plasma volume = 6.4 L x 0.55 = 3.52 L.

Equations

Conc = Dose / V

V = Dose/Conc

Distribution QuestionExample 4

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 =

Equations

Conc = Dose / V

V = Dose/Conc

Distribution QuestionExample 4

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/LAmount in body =

Equations

Conc = Dose / V

V = Dose/Conc

Distribution QuestionExample 4

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)

Equations

Conc = Dose / V

V = Dose/Conc

Distribution QuestionExample 4

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 ?=

Equations

Conc = Dose / V

V = Dose/Conc

Distribution QuestionExample 4

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%

Equations

Conc = Dose / V

V = Dose/Conc

Distribution QuestionExample 4

Volume of Distribution

Blood

Liver

Kidney

GI TractOralDose

IVDose

Fifth Example: Cyclosporin

Cyclosporin (CsA), 600 mg isadministered 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 bloodsample is taken and the blood concentrationis 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

Cyclosporin (CsA), 600 mg isadministered to a female transplantpatient – 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 bloodsample is taken and the blood concentrationis measured as 200 ng/mL. (200 ug/L)

(a) What is the apparent volume of distrib?Conc = Dose / VolumeVolume = Dose / Conc

=

Equations

Conc = Dose / V

V = Dose/Conc

A Fifth Example - cyclosporin

Cyclosporin (CsA), 600 mg isadministered to a female transplantpatient – 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 bloodsample is taken and the blood concentrationis measured as 200 ng/mL. (200 ug/L)

(a) What is the apparent volume of distrib?Conc = Dose / VolumeVolume = Dose / Conc

= 600 mg / 200.0 ug/L= 600 mg / 0.2 mg/L= 3,000 liters

Equations

Conc = Dose / V

V = Dose/Conc

A Fifth Example - cyclosporin

Cyclosporin (CsA), 600 mg isadministered to a female transplantpatient – 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 bloodsample is taken and the plasma concentrationis measured as 100 ng/mL. (100 ug/L)

(a) What is the apparent volume of distrib?Conc = Dose / VolumeVolume = Dose / Conc

=

Equations

Conc = Dose / V

V = Dose/Conc

A Fifth Example - cyclosporin

Cyclosporin (CsA), 600 mg isadministered to a female transplantpatient – 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 bloodsample is taken and the plasma concentrationis measured as 100 ng/mL. (100 ug/L)

(a) What is the apparent volume of distrib?Conc = Dose / VolumeVolume = Dose / Conc

= 600 mg / 100.0 ug/L= 600 mg / 0.1 mg/L= 6,000 liters

Equations

Conc = Dose / V

V = Dose/Conc

A Fifth Example - cyclosporin

Equations

Conc = Dose / V

V = Dose/Conc

A Fifth Example - cyclosporin

Cyclosporin (CsA), 600 mg isadministered to a female transplantpatient – 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 bloodsample is taken and the blood concentrationIs 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 weightMs. MJ weighs 55 kg. MJ’s hematocrit is 0.45 (45% cells)

Blood Volume=

Cyclosporin (CsA), 600 mg isadministered to a female transplantpatient – 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 bloodsample is taken and the blood concentrationIs 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 weightMs. MJ weighs 55 kg. MJ’s hematocrit is 0.45 (45% cells)

Blood Volume= 55 kg x 0.08= 4.4 L

Equations

Conc = Dose / V

V = Dose/Conc

A Fifth Example - cyclosporin

Cyclosporin (CsA), 600 mg isadministered to a female transplantpatient – 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 bloodsample is taken and the blood concentrationIs 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 LHow much is in Blood?

=

Equations

Conc = Dose / V

V = Dose/Conc

A Fifth Example - cyclosporin

Cyclosporin (CsA), 600 mg isadministered to a female transplantpatient – 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 bloodsample is taken and the blood concentrationIs 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 LHow much is in Blood?

= 4.4 L x 0.2 mg/L= 0.88 mg

How much is in the body?Amount in body =

Equations

Conc = Dose / V

V = Dose/Conc

A Fifth Example - cyclosporin

Cyclosporin (CsA), 600 mg isadministered to a female transplantpatient – 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 LHow 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 ?

Equations

Conc = Dose / V

V = Dose/Conc

A Fifth Example - cyclosporin

Cyclosporin (CsA), 600 mg isadministered to a female transplantpatient – 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%

Equations

Conc = Dose / V

V = Dose/Conc

A Fifth Example - cyclosporin

Cyclosporin (CsA), 600 mg isadministered to a female transplantpatient – 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 bloodsample is taken and the plasma concentrationis 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 LHow much is in plasma?

=

Equations

Conc = Dose / V

V = Dose/Conc

A Fifth Example - cyclosporin

Cyclosporin (CsA), 600 mg isadministered to a female transplantpatient – 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 bloodsample is taken and the plasma concentrationis measured as 100 ng/mL.

(a) What percent of CsA in the body is located in plasma in this patient?Plasma Volume = 2.42 LHow much is in Plasma?

= 2.42 L x 0.1 mg/L= 0.242 mg

How much is in the body?Amount in body =

Equations

Conc = Dose / V

V = Dose/Conc

A Fifth Example - cyclosporin

Cyclosporin (CsA), 600 mg isadministered to a female transplantpatient – 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 LHow 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 ?

Equations

Conc = Dose / V

V = Dose/Conc

A Fifth Example - cyclosporin

Cyclosporin (CsA), 600 mg isadministered to a female transplantpatient – 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%

Equations

Conc = Dose / V

V = Dose/Conc

A Fifth Example - cyclosporin

Comparison Blood : Plasma

Concentration (ng/mL) 200100

Tissue Volume (L) 4.42.42

Amount in Tissue (mg) 0.88 0.242App Vol. Dist. (L) 3,000

6,000Dose (mg) 600 600Percent in blood/plasma (%) 0.15 0.04

A Fifth Example - cyclosporin

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

Comparison Blood : Plasma

Concentration (ng/mL) 200100

Tissue Volume (L) 4.42.42

Amount in Tissue (mg) 0.88 0.242App Vol. Dist. (L) 3,000

6,000Dose (mg) 600 600Percent in blood/plasma (%) 0.15 0.04

A Fifth Example - cyclosporin

Does the difference in apparent volumes imply anything about where cyclosporin distributes to?

If you are told*(published knowledge: ~ MIC, ED

, 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)

~ 0.88 mg

50

General Principles of Distribution

Summary1. 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