SL011 Distribution Lectures

Question 1

Why is blood distribution faster than tissue distribution?

Answer 1

Blood distribution is dependent on the mechanisms of the circulatory system (pressure differential, heart rate etc.)

Tissue distribution is dependent on diffusion or some other slow form of transport.

Question 2

What does ISF stand for?

Answer 2

Interstitial fluid

Question 3

What factors is distribution between blood and ISF mainly dependent on?

Answer 3

Not much, relatively easy. Charge becomes relevant in larger molecules.

Question 4

What factors is distribution between ISF and intracellular fluid dependent on?

Answer 4

Drug physicochemical properties (size charge, lipophilicity)

Whether the drug is a substrate for influx/efflux

Question 5

How would a high pH influence the distribution of a weakly acidic drug?

Answer 5

If a drug is weakly acidic and exposed to a high pH, it will ionise. Thus, reducing the capability of the drug to undergo membrane transport.

Question 6

What does the pH-partition hypothesis state?

Answer 6

Net flow of the drug across the membrane will become zero once the unionised quantity of the drug on both sides of the membrane is equal.

Question 7

3 main things about transporters relevant to drug distribution?

Answer 7

Two types of transporters: equilibrating or active/concentrating

Pumps can be efflux or influx

Can be located on the apical side or basolateral side

Question 8

Apical side?

Answer 8

The lumen side

Question 9

Basolateral side?

Answer 9

The blood side

Question 10

What is the general effect of lipophlicity on drug transport?

Answer 10

Greater lipophilicity increases drug transport

Question 11

How does the BBB reduce the net transport of toxic or dangerous molecules?

Answer 11

Many efflux pumps to ensure drugs have a low CSF concentration.

Question 12

How does plasma protein binding prevent the distribution of a drug?

Answer 12

Overall molecular weight of the drug when bonded to the protein is too great to diffuse or be transported across membranes.

Question 13

Formula for the bound fraction. How can you obtain the free or unbound fraction from this?

Answer 13

fbound = [drug]bound/[drug]total

1-fbound = funbound

Question 14

What’s the central principle for drug binding equilibrium?

Answer 14

The unbound portions of the drug will equilibrate across the tissue and the plasma, appearing in equal concentrations.

Question 15

What’s the equation for drug binding equilibria?

Answer 15

Cunbound tissue = Cunbound plasma

Question 16

How can the overall concentration of a drug differ across tissues and plasma?

Answer 16

Portions of the drug may be bound to plasma proteins or tissue factors. Only the unbound portions of the drug equilibrate.

Question 17

State the tissue partition coefficient equation

Answer 17

Ptissue/blood=Cdrug,tissue/Cdrug,plasma

Question 18

State the formula for the volume of distribution

Answer 18

V = A/Cp

Question 19

Define the volume of distribution

Answer 19

The apparent volume into which a drug distributes in the body once the equilibrium of distribution has been achieved.

Question 20

Would the volume of distribution be larger or smaller for a drug that mostly distributes into the tissue? Why?

Answer 20

It would be larger since less of the total drug would reside in the plasma. Thus, the apparent volume would require a greater value since its based off of the plasma concentration.

Question 21

What is volume of distribution used for?

Answer 21

1. To relate the amount of drug in the body with the drug plasma concentration
2. Estimate the dose required to achieve a given concentration (Crequired)

Question 22

State the dose equation

Answer 22

Dose = V*Crequired

Question 23

State the formulae for unbound fraction in plasma and tissue

Answer 23

fu = Cu/Cp and futissue =Cu/Ctissue

Question 24

State the formula linking volume of distribution and drug binding

Answer 24

V = Vp+Vt*(fu/futissue)

Question 25

State the equation linking volume of distribution and partition coefficient. Why does this equation involve summation?

Answer 25

V = Vp + SUM of (Vt*P) Vt*P must be repeated for the volume residing in each tissue that the drug is associated with, this in turn dictates a partition coefficient for each tissue.

Question 26

State the equation for percentage of a drug present in plasma. How can we use this to determine the percentage in tissues?

Answer 26

(Vp/V)*100 = %plasma To obtain %tissues replace Vp with V-Vp

Question 27

When does the volume of distribution and drug binding equation become relevant?

Answer 27

When there is an alteration to the distribution of a drug and we want to see how it's affected drug binding. IMPORTANTLY, when there is an alteration to drug binding, and we want to see how it's affected the distribution of a drug SUCH AS WHEN A SECOND DRUG BINDS TO THE SAME RECEPTORS.

Question 28

What are the rate-limiting factors of drug distribution?

Answer 28

Perfusion rate limited Permeability rate limited

Question 29

What's the rate-limiting step for polar drugs?

Answer 29

Permeability across lipophilic membranes

Question 30

What's the rate-limiting step for small and lipophilic drugs?

Answer 30

Perfusion throughout the blood stream

Question 31

What factors affect permeability rate-limited distribution?

Answer 31

1. Changes in membrane permeability 2. Drug properties (which affect partition)

Question 32

What factors affect perfusion rate-limited distribution?

Answer 32

Blood flow to the specific tissue (highly perfused or lowly perfused) Changes in overall blood flow

Question 33

State the equation for rate of uptake

Answer 33

Rate of uptake = Q(Ca-Cv) Where Q = Blood flow a and v mean artery and vein

Question 34

State the tissue distribution rate constant equation. State the tissue distribution half life equation.

Answer 34

Kt = (Q/Vt)/P t1/2 = 0.693/Kt

Question 35

Amount of drug in tissue equation

Answer 35

Vt*Ct = Vt*P*Cv