Volume of distribution

Question 1

What is the extent of distribution defined by?

Answer 1

Apparent volume of distribution (Vd), based on equilibrium concept

Question 2

What does the volume of distribution equal?

Answer 2

V = A/C

A - Amount of drug in the body at equilibrium
C - measured plasma drug concentration

Question 3

Why might the same dose for 3 different drugs achieve very different plasma concentrations?

Answer 3

All 3 drugs have different volumes of distribution

Question 4

What is the apparent volume of distribution (Vd) equal to?

Answer 4

Vd = (Amount of drug in the body at equilibrium)/(Drug concentration in the plasma)

Question 5

What is apparent volume of distribution?

Answer 5

The apparent volume that the drug occupies at a concentration equal to that in plasma.

*note: refers to not a physical but an APPARENT volume. The value depends on the reference fluid measured (plasma, blood, plasma water (unbound drug conc)

Question 6

What is the approximate value of plasma water in the body?

Answer 6

3L

Question 7

What is the approximate value of extracellular water in the body?

Answer 7

12L

Question 8

What is the approximate value of the total body water?

Answer 8

40L

Question 9

At equilibrium what does the amount of drug in the body (A) equal?

Answer 9

A=V.C=Vb.Cb=Vu.Cu

amount=plasma=blood=plasma water

Question 10

What does the volume of distribution NOT tell you?

Answer 10

WHERE it has been distributed

Question 11

What Volume of distribution do mAbs have?

Answer 11

Very low volume of distribution - reside in the plasma

Question 12

What volume of distribution do acidic drugs (warfarin, tolbutamide) tend to have?

Answer 12

Acidic drugs are highly ionised and bind to plasma proteins extensively so generally have a low volume of distribution

Question 13

What volume of distribution do basic drugs (fluoxetine) tend to have?

Answer 13

High volume of distribution - accumulate in tissues and bind to acidic phospholipids

Question 14

What does the fraction of drug in body in plasma equal?

Answer 14

= Vp/V
Vp - plasma volume (3L)

*note both are multiplied by C but cancel each other out

Question 15

What is the relationship between the volume of distribution and fraction of drug in the plasma?

Answer 15

The higher the volume of distribution, the fraction in the plasma is smaller

Question 16

What does the fraction of drug in body outside of plasma (including blood cells) equal?

Answer 16

= V-Vp/V = 1-Vp/V

Question 17

What are lysosomes?

Answer 17

Acidic organelles (pH 4-5)

Question 18

Describe lysosomal trapping:

Answer 18

• A basic unionised drug crosses the membrane into cytosol (pH 7-7.4) and gets into the lysosome
• Because the pH is more acidic, the basic molecule will become ionised
• Protonated form becomes the DOMINANT form
• Protonated form cannot diffuse back into the cytosol

*SUBCELLULAR DISTRIBUTION

Question 19

What organs/tissues have a large proportion of lysosomes?

Answer 19

Macrophages in the lungs and liver

Question 20

In what case is lysosomal trapping beneficial?

Answer 20

For antimalarial drugs (e.g. chloroquine), they target the lysosomes of particular cells

Question 21

Generally, is lysosomal trapping good or bad?

Answer 21

Generally bad, as we want effects in the cytosol, not the lysosome. E.g. antibiotic resistance linked to extensive accumulation in the lysosomes

Question 22

What is a safety concern for lysosomal trapping?

Answer 22

Phospholipidosis - extensive accumulation in lysosomes

Question 23

What protein do acidic drugs bind to?

Answer 23

Albumin

Question 24

What protein do basic drugs bind to?

Answer 24

alpha1 - Acid glycoprotein

Question 25

What do steroids bind to?

Answer 25

globulins

Question 26

What is fu?

Answer 26

Fraction of drug unbound in plasma

Question 27

How do you work out fraction of drug bound?

Answer 27

1-fu

Question 28

What does fu depend on?

Answer 28

o Affinity of the protein for the drug defined by the dissociation constant (Ka)
o Protein and drug concentration

Question 29

Why is knowing fu important?

Answer 29

• When fu is constant, changes in TOTAL plasma concentration reflect changes in the UNBOUND drug calculation (C=Cu/fu)