E1 L2: Drug Distribution

Question 1

Passive diffusion properties

Answer 1

Drug passes down concentration gradient
Not saturated
Most common

Question 2

Transcellular junctions

Answer 2

Cross lipid bilayer (go through)

Question 3

Paracellular diffusion

Answer 3

Go between (for hydrophilic small molecules)

Question 4

Facilitated diffusion

Answer 4

Down concentration gradient
Via carriers
Saturable
E.g. Organic anion transporting polypeptides (OATP)

Question 5

Active transport

Answer 5

Against concentration gradient
Via transporter
Uses ATP (energy)
Saturable
Ex. P-glycoprotein

Question 6

Passive diffusion graphed

Answer 6

Increases linearly with concentration

Question 7

Carrier mediated transport graphed

Answer 7

Curved - too much drug in system = saturation (saturated at high drug concentrations)

Question 8

Passive diffusion:
Involvement of a protein channel or transporter?
Saturable?
Direction?
ATP Use?

Answer 8

No
No
High to low conc
No

Question 9

Passive FACILITATED diffusion:
Involvement of a protein channel or transporter?
Saturable?
Direction?
ATP Use?

Answer 9

Yes
Yes
High to low
No

Question 10

Active Transport:
Involvement of a protein channel or transporter?
Saturable?
Direction?
ATP Use?

Answer 10

Yes
Yes
Low to high
Yes

Question 11

Factors determining diffusion

Answer 11

Molecular size - poor permeability for large molecules
Lipophilicity - poor permeability for hydrophilic molecules

Question 12

Indicator of compound lipophilicity
The larger, the more lipophilic (hydrophobic)

Answer 12

LogP

Question 13

Best permeability has..

Answer 13

Small MW
Large LogP

Question 14

Factors determining diffusion

Answer 14

Molecular size
Lipophilixty
Charge

Question 15

Q: T/F: Salicylic acid will exhibit better crossing through the lipid bilayer at higher pH (ie. in basic condition)

Answer 15

False - higher pH = ionized= worse permeability

Question 16

Perfusion rate limited

Answer 16

Only limiting factor- rate of blood flow

Question 17

Permeability rate limited

Answer 17

Do not cross membrane readily

Question 18

Perfusion rate limitation: hydrophobic or hydrophilic?

Answer 18

Hydrophobic (rate of blood flow)

Question 19

Permeability rate limitation: hydrophobic or hydrophilic?

Answer 19

Hydrophilic (does not readily cross membrane)

Question 20

Perfusion vs. Permeability rate limited graphed

Answer 20

Perfusion: High concentration (more lipophilic)
Permeability (low line)

Question 21

Q: which of the following would have a faster propofol distribution (nonpolar lipophilic - LOG P = 3.79)
Brain: perfus rate: 0.5
Muscle: Perfus rate 0.025

Answer 21

Brain - Compound is perfusion rate limited
Small compound that distributes perfusion rate limited

Question 22

Major drug binding plasma proteins

Answer 22

ALBUMIN
a1-acid glycoprotein
Lipoproteins

Question 23

Most abundant plasma protein
Produced in the liver
Binds FFA, hormones, and weakly acidic (anionic) drugs
Main function - maintain oncotic pressure of blood
Serum levels decreased in liver and kidneys

Answer 23

Albumin

Question 24

AKA orosomucoid
Produced in liver
Binds primarily weak basic (cationic) drugs such as tertiary and quaternary amines
Serum levels increase during acute phase reaction, e.g. inflammation and burns
Serum levels are decreased in liver and kidney diseases

Answer 24

a1-Acid glycoprotein (AAG)

Question 25

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

Answer 25

Lipoproteins

Question 26

Free drug hypothesis:

Answer 26

Only free drug exists capillaries to reach extravascular sites of action Only free (unbound) drug crosses cell membrane via diffusion Only free (unbound) drug binds to transporters

Question 27

T/F: Plasma protein binding of drugs is reversible

Answer 27

True

Question 28

Plasma makes up how much of the total blood volume?

Answer 28

50%

Question 29

Coagulated blood that settles at the bottom of the tube

Answer 29

Serum

Question 30

Serum is devoid of

Answer 30

Blood cells Fibrin Clotting factors

Question 31

Serum contains

Answer 31

Plasma proteins (like albumin)

Question 32

Unbound fraction

Answer 32

Free drug concentration/Total concentration

Question 33

Determinants of Vd

Answer 33

V = Vp + VTW * fu/Fut

Question 34

Q: T/f: Ionized compounds show poorer membrane permeability than unionized compound

Answer 34

True

Question 35

Q: T/F: Lipophilic compounds tend to show greater membrane permeability

Answer 35

True

Question 36

Q: T/F: Lipophilic compounds tend to show permeability rate-limited distribution

Answer 36

False (lipophilic=diffusion rate limited)

Question 37

Q: T/F: Decreased plasma protein binding of high protein bound drugs will likely increase Vd

Answer 37

True

Question 38

Q: T/F: Vd is expected to be small for a drug that exhibits strong binding to tissue components

Answer 38

False - (goes up)