Lecture 3 - Distribution Concepts

Question 1

(T/F): Drug can still pass through freely via the BBB.

Answer 1

False, there is a limitation in the ability of the drug to pass through a lipid barrier like the BBB.

Question 2

(T/F): Movement of drugs across a membrane depends solely on the influence of pH, according to the pH partition hypothesis.

Answer 2

False, membrane characteristics play an important role in determining the movement of drugs as well.

1. tight junctions (BBB and gastric epithelial cells) vs fenestrations (blood capillaries and renal glomerular membrane).
2. membrane thickness
3. carrier-mediated transport

Question 3

_____ and ____ drugs can permeate the membrane via _________.

Answer 3

Unbound, unionised, passive transcellular pathway

Question 4

Define apparent volume of distribution.

Answer 4

Fluid volume that the drug seems to be distributed in to account for its plasma concentration.

Question 5

Distribution is influenced by ____, ____ and ____.

Answer 5

Log P value, pKa, and physiological pH

Question 6

How can we prevent a phenobarbital overdose (logP = 1.5, pKa = 7.3 (weak acid), long half-life = 2-7 days)?

Answer 6

Make the circulation pH less alkaline/more acidic, so that there will be a higher fraction of unionised drug and less of the drug will permeate the tissues,

Question 7

How to calculate the fractional rate of distribution?

Answer 7

fractional rate of distribution = rate of presentation / amount in tissue = (Q/Vt) / KPb

Question 8

How to calculate tissue distribution half-life?

Answer 8

Tissue distribution half-life = (In 2. KPb) / (Q/Vt)

Question 9

How to determine volume of distribution, V?

Answer 9

Extrapolate drug to find C0.
Take Dose/ Co to get V in litres.

Alternatively, to calculate V:
V = Vp + VTKp (apparent volume of distribution)

Question 10

Name the 4 stages of administration following rapid IV injection:

Answer 10

Divided by the MEC:
Stage I: post-iv administration (near C0)
Stage II: distribution
Stage III: distribution equilibrium (at inflection point)
Stage IV: elimination predominates

Question 11

Name the factors affecting the rate of distribution.

Answer 11

1. Perfusion rate limitation

2. Permeability rate limitation

Question 12

Name the various transport mechanisms.

Answer 12

1. Passive transcellular diffusion
2. Carrier-mediated transport
   A. Passive facilitated diffusion
   - no ATP expenditure
   - equilibrium of both aqueous phases can be reached.
   B. Active Transport
   - ATP expenditure
   - Use of transporters like ATP and MDR1

Question 13

What are some membrane characteristics that can affect the movement of drugs across the membrane?

Answer 13

1. Thickness of membrane barrier (the thicker the membrane, the lower the permeability)
2. Nature of the membrane (tight junctions in the BBB and epithelial cells vs loose fenestrations in the capillaries and the renal glomerular membrane)
3. Presence of efflux transporters (if drugs are a substrate of them, permeability will be low).

Question 14

What are the assumptions for the percentages of total body water and extracellular water as mentioned previously?

Answer 14

1. No efflux transporters

2. No binding of drug to plasma and tissue proteins

Question 15

What is the percentage of total body water and extracellular water in a 70kg man?

Answer 15

Total body water: 60% (42kg)

Extracellular water: 20% (14kg)

Question 16

What is the relationship between BBB permeability and logP value?

Answer 16

The higher the logP value, the less lipophilic the compound, the greater affinity it will have with the aqueous phase, and the higher the BBB permeability.

Question 17

When do we use perfusion rate limitation, and how is it expressed as?

Answer 17

• when the membrane poses no significant barrier to the transport of drugs.
• expressed as mL. min-1. g-1, or mL. min-1. mL-1 if density is known.

Question 18

When do we use permeability rate limitation?

Answer 18

when cell membrane resistance to drug transport is high because of:

• membrane properties (as elaborated upon earlier)
• large and polar drugs

Question 19

Why are vincristine and vinblastine exceptions?

Answer 19

• Vincristine and vinblastine have high logP values but low permeability.
• They are likely to be substrates of efflux transporters (e.g. P-gp, MDR1).

Question 20

Why does carrier-mediated transport have a lower initial rate of transport and plateaus after a while, while passive diffusion keeps increasing?

Answer 20

• Large, bound and ionised molecules usually pass through the membrane via carrier-mediated transport, which are slower in transport than unbound and unionised molecules.
• Carrier proteins reach saturation after a while.

Question 21

Why does thiopental have a better rate of distribution than salicylic acid?

Answer 21

It has a higher fraction unionised at physiological pH, and has a higher pKa than salicylic acid.