Drug Distribution Review

Question 1

What are the key components of passive diffusion?

Answer 1

• Going down the concentration gradient (high to low)
• Not saturated
• Most common

Question 2

What are the two types of carrier mediated transport?

Answer 2

• Facilitated diffusion
• Active Transport

Question 3

Describe paracellular transport.

Answer 3

Paracellular transport is the movement of substances between adjacent cells, rather than through them. This process occurs across tight junctions that connect epithelial or endothelial cells and is primarily passive.
* Transport of the blood between tissues/cells
* For hydrophillic small molecules (uncharged)

Question 4

How does transcellular differ from paracellular transport?

Answer 4

Transcellular- through the cell

Question 5

What are the key components of facilitated diffusion?

Answer 5

• Not ATP dependent
• Down concentration gradient
• Via carriers
• Saturatable- only so many carriers for the drug conc.
• Ex. organic anion transporting polypeptides (OATP).–> Pravastatin

Question 6

What are the key components of active transport?

Answer 6

• Against conc. gradient
• Via transporter
• Uses ATP
• Saturatable- only so many carriers for the drug conc.
• Ex. P-glycoprotein–> Vincristine

Question 7

When is carrier-mediated transport saturated?

Answer 7

When there is a high drug concentration.

Question 8

What factors determine diffusion?

Answer 8

• Molecular size
• Lipophilicity
• Charge

Question 9

How does molecular size impact diffusion?

Answer 9

• Poor permeability for large molecules.

Question 10

How does lipophilicity impact diffusion?

Answer 10

• poor permeability for hydrophilic molecules.

Question 11

What is LogP?

Answer 11

• An indicator of compound lipophilicity
• The higher the LogP value, the more lipophilic or hydrophobic the molecules are.

Question 12

How does charge impact diffusion?

Answer 12

• There is poor permeability for charged molecules.

Question 13

How does ionized or unionized impact the diffusion?

Answer 13

Ionized compounds show poorer permeation through membrane
compared to un-ionized compounds

Question 14

What is the rate limiting factor for distribution for small, lipophilic molecules?

Answer 14

The rate limiting step for drug distribution is the amount of blood carrying the drugs away. More blood=more distribution?

Perfusion-rate limited

Question 15

What is the rate limiting factor for distribution for small, hydrophilic molecules?

Answer 15

Rate-limiting step for drug distribution is the slow rate of drug passing the cell membrane.

Permeability-rate limited

Question 16

Given the following information, would the brain or muscle show faster propofol distribution?

Propofol
* General anesthesia-inducing agent
* Non-polar lipophilic compound (LogP=3.79)
* Distribution is PERFUSION-rate limited.

Brain
* Perfusion rate: 0.5 mg/min/g tissue

Muscle
* Perfusion rate: 0.025 ml/min/g tissue

Answer 16

The brain has a much higher perfusion rate than muscle (20 times higher). Therefore, propofol will distribute faster into the brain compared to muscle.

Simple: The higher the perfusion rate, the faster the drug is recieved in the tissue.

Question 17

What are the major drug-binding plasma proteins?

Answer 17

• Albumin
• alpha1-acid glycoprotein
• Lipoproteins

Question 18

What are the characteristics of the binding-protein albumin?

Answer 18

• The most abundant plasma protein (50% of human plasma proteins)
• Produced in the liver
• Binds free fatty acids, hormones, and weakly acidic (anionic) drugs.
• Main fxn is to maintain the oncotic pressure of blood.
• Serum levels are decreased in liver and kidney diseases.

Question 19

What are the characteristics of the binding-protein α1-Acid glycoprotein (AAG)?

Answer 19

• Known as orosomucoid
• Produced in the liver
• Binds primarily weakly basic (cationic) drugs such as tertiary and quaternary amines
• Serum levels increase during acute phase reaction (inflammation and burns)
• Serum levels are decreased in liver and kidney diseases.

Question 20

What are the characteristics of the binding-protein called lipoproteins?

Answer 20

• Lipophyllic protein and/or a complex of proteins and lipids.
• Includes HDL and LDL
• Binds hydrophobic drugs
• Altered in some disease states, including heart disease.

Question 21

What are the five components of the free drug hypothesis?

Answer 21

• Only free (unbound) drug exits capillaries to reach extravascular sites of action.
• Only free (unbound) drug crosses cell membrane via diffusion.
• Only free (unbound) drug binds to transporters
• Only free (unbound) drugs cross the cell membrane and are eliminated.
• Generally, the more lipophilic a compound is, the better its albumin binding is.

Ex. Liraglutide is more lipophilic than Exenatide, so it has a greater binding to albumin, and a much longer half-life.

Question 22

Is the plasma protein binding of drugs irreversible?

Answer 22

No; It is reversible.

Question 23

At equilibrium, how much of the free drug is on the both sides of the membrane?

Answer 23

The same on both sides

Question 24

Where do we measure drug concentration in the blood?

Answer 24

The plasma

Question 25

What is blood plasma?

Answer 25

* The liquid component of the blood, in which the blood cells are suspended (yellow colored). * Plasma make up about 55% of the total blood volume.

Question 26

What proteins does plasma contain?

Answer 26

Fibrinogen, globulins, and albumin

Question 27

How is blood serum different than blood plasma?

Answer 27

* Serum: the liquid portion of the blood AFTER clotting * Plasma: the liquid portion of the blood BEFORE clotting

Question 28

What is serum?

Answer 28

The supernatuant fluid of the blood produced after the blood clotting occurs at the bottom of the tube.

Question 29

Are there any clotting factors in serum?

Answer 29

NO! The serum is devoid of blood cells, fibrin, and clotting factors. This is because the factors were already used in the clotting. However, serum contains plasma proteins like albumin still.

Question 30

How do we estimate fu through ultrafiltration?

Answer 30

The fraction unbound (fu) of a drug in plasma or serum can be estimated using ultrafiltration, which separates free (unbound) drug from protein-bound drug based on size exclusion.

Question 31

What does C stand for?

Answer 31

Total drug concentration * Measure drug concentration after sample processing to etract both protein-bond and free drug molecules.

Question 32

What does Cu stand for?

Answer 32

Free (unbound)drug concentration * Measure drug concentration after sample processing to exlude protein-bound drug molecules.

Question 33

Fu= | In terms of concentration

Answer 33

Fu= Cu/C

Question 34

What equation do we use to calculate the total volume of distribution (V(C)) for a drug?

Answer 34

V(C) = Vp(C) + VTW(CTW) * Vp(C)- the volume of plasma where the drug is initally distributed after administration * VTW(CTW)- The drug distributed into tissue water. * Overall, this equation means theat the total volume of distribition is the sum of the plasma volume and the tissue water volume influenced by the drug concentration.

Question 35

fut=

Answer 35

fut= Cut/Ctw | In terms of concentration

Question 36

# What does changing the variables below do to the volume (d)? V= Vp + VTW(Fu/Fut)

Answer 36

* The volume of distribution increases when Fu is increased * The volume of distribution decreases when Fut is increased.

Question 37

How would decreased plasma protein binding impact the concentration of free drug in the blood?

Answer 37

* The concentration of free drug increases in the blood with less plasma binding. * This results in larger volume of distribution.

Question 38

What does significant drug tissue protein binding cause?

Answer 38

* Lower free drug concentration in tissue * Larger volume of distribution.