Pharmacokinetics 2: Drug Distribution

Question 1

How are drugs distributed?

Answer 1

Tranditional view: Passive diffusion and strongly influenced by its physicochemical properties.

Binding to proteins in plasma vs tissues is important and blood flow plays a vital role in exposing tissues to circulating drugs.

Emerging view is that drug transporters strongly regulate drug distribution:
SLC transporters move drugs between compartments into tissues. ABC transporters mainly move drugs out of tissues.

Question 2

What factors influence drug distribution?

Answer 2

Blood flow to particular tissues.

Size of tissues

Binding to plasma proteins

Binding to tissue proteins

Permeability of tissue membranes

Presence of protein transporters on membrane of target tissues.

Question 3

Where do oral drugs go immediately after absorption?

Answer 3

The liver

Question 4

Which tissues get more drug?

Answer 4

More well-perfused tissues such as lungs, liver and kidneys.

Question 5

How do drugs move through capillary walls?

Answer 5

Through fenestrations on capillaries (average gap of 4nm). Most drugs are smaller than this.

Question 6

What does drug penetration ensure?

Answer 6

Ready access to drug receptors on cell surfaces.

Question 7

What is the main barrier to substance exchange by diffusion?

Answer 7

The basal membrane.

Question 8

What molecules can pass easily through basement membrane?

Answer 8

Molecules smaller than 10 kDa

Question 9

What replaces fenestrations in brain capillaries?

Answer 9

Tight junctions

Question 10

What influences where around tissues the drug accumulates?

Answer 10

Their mass, polarity, and lipophilicity

Question 11

Where do drugs accumulate in tissues?

Answer 11

Intracellularly

Within interstitial fluid

or in Fat

Question 12

What does the volume of distribution tell us?

Answer 12

It provides information about how the drug is distributed if we assume the body behaves as one homogenous compartment.

Question 13

What is the formula for V distribution?

Answer 13

Dose/plasma concentration

Question 14

What happens in reality to drug distribution?

Answer 14

Its distribution would usually reflect plasma concentrations within the body.

Question 15

What is the one compartment model of drug distribution?

Answer 15

Drug is evenly distributed throughout the body.

Question 16

What is the two-compartment model of drug distribution?

Answer 16

Drug in blood stream is lost to another peripheral compartment

Question 17

What does Vdist tell us?

Answer 17

It tells us how the drug behaves during the distribution phase.

A high Vdist means the drug accumulates in the tissues rather than the blood

A low Vdist means the drug accumulates in the blood rather than in tissues.

Question 18

How is water distributed in the body?

Answer 18

4.5 - 5L in blood [3L plasma 2L within blood cells]

12L interstitial water

27L intracellular water.

Plasma + interstitial water make up 15 L extracellular water

Question 19

What must occur for a drug to stay within the plasma?

Answer 19

Either it is very big or it has strong plasma protein binding properties

Question 20

Where do hydrophilic and hydrophobic drugs tend to penetrate?

Answer 20

Within interstitial fluid as lipophilicity increases they can penetrate intracellular space and tissues.

Highly lipophilic drugs can penetrate fat and muscle

Question 21

When is a high volume of distribution useful?

Answer 21

When trying to access tissues that are hard to access such as muscles and skin.

Question 22

When is a low volume of distribution useful?

Answer 22

When trying to keep drug within the blood plasma

Question 23

What is the concentration of plasma protein on average in plasma? What is the function of plasma protiens?

Answer 23

Plasma contains 60 - 80g protein/L. Plasma proteins serve as carriers for natural compounds plus many drugs.

Question 24

What plasma protein do acidic drugs bind to?

Answer 24

Albumin

Question 25

What plasma protein do basic drugs bind to?

Answer 25

Alpha1-glycoprotein.

Question 26

Can drug bound to transport protein carry out its function? What does this mean?

Answer 26

No it must be free (unbound). Higher doses are needed for therapeutic effect.

Question 27

What undesirable outcome can occur from plasma protein binding?

Answer 27

Competition between drugs may cause DDIs

Question 28

What does transport protein binding do to drug clearance?

Answer 28

It slows clearance down

Question 29

Which drugs bind to plasma proteins?

Answer 29

Lipophilic drugs (i.e drugs with high logP)

Question 30

How big is albumin?

Answer 30

65 kDa monomer

Question 31

What are tissue proteins important for?

Answer 31

They can bind drugs at certain concentrations at equilibrium

Question 32

Examples of drug-binding tissue proteins:

Answer 32

Albumin

Ligandin (liver kidneys intestines)

Myosin and actin

Melanin

Question 33

What proportion of CNS potential drugs fail to penetrate BBB?

Answer 33

98%

Question 34

Which drugs can be stored in fat?

Answer 34

Only highly lipophilic drugs

Question 35

Which drugs can be present for a long time in fat? What does this mean?

Answer 35

Only highly lipophilic drugs (eg. THC and anabolic steroids)

Drugs can accumulate in fatty tissue and this can result in complications of high drug concentrations.

Question 36

Which common drugs have high fat partitioning?

Answer 36

Volatile anaesthetic agents

Question 37

How does the liver detoxify so many foreign material?

Answer 37

It has many diverse influx receptors that allow uptake of drug.

Question 38

Which transporters are important for metformin transport into the liver? What happens in KO mice of this receptor?

Answer 38

OCT1/2, they had lower Vdist of metformin meaning more metformin was present in the blood.

Question 39

Where can drugs accumulate after absorption?

Answer 39

A) Transport protein binding

B) Tissue protein binding

C) Brain penetration

D) Partitioning into fat