3: absorption - membrane transport

Question 1

Paracellular vs transcellular

Answer 1

paracellular: has less exposed area and is limited by drug size and solubility in water.
transcellular: has more exposed surface area, but limited to drugs that can pass the cell membrane.

Question 2

Define Fick’s Law

Answer 2

The rate of passive diffusion of a molecule through the membrane.
Factors: concentration gradient, membrane properties (thickness, SA), drug properties (lipid solubility, pH partitioning)

Question 3

Define each term in Fick’s Law:
dM/dt = [(DAmKm)/hm] * (Cout - Cin)

Answer 3

dM/dt = diffusion rate
D = diffusion coefficient of drug in membrane (how fast the drug will move within the media)
Am = membrane area
Km = membrane/water partition coefficient (ability to jump from one phase to another (membrane/oil phase)
Cout/Cin = drug concentration in solution at “steady state”
hm = thickness of the membrane

Question 4

How do you measure partition coefficient?

Answer 4

[drug oil phase] / [drug water phase ]

Question 5

Based on Fick’s law, which of the following properties will NOT promote rapid absorption of drugs?
a) high drug solubility
b) large surface area
c) high viscosity
d) lipophilic

Answer 5

c) high viscosity

Question 6

how do you calculate permeability?

Answer 6

P = (D*Km)/hm

Question 7

Is an ionized drug hydrophobic or hydrophilic? An unionized drug?

Answer 7

An ionized drug is hydrophilic.
Unionized drug is hydrophobic

Question 8

Explain the concept of ion trapping

Answer 8

Ion trapping means that strong acids in the stomach push “weak acid drugs” through a charge selective membrane into the blood without using energy.

Since we have a charge selective membrane, UNCHARGED molecules are able to pass through the membrane and CHARGED molecules can’t.

Question 9

Equation to calculate ionization

Answer 9

I = U * 10^(pH-pK)
i - ionized
u - unionized

Question 10

How do you use the ionization equation properly?

Answer 10

make sure to plug in 1 for U and then solve for I
(U is insignificant bc it is so small in relation)

Question 11

How to find fraction ionized?

Answer 11

I/(I+U)

Question 12

If Km = 0, will there be any flux? How will they get absorbed then?

Answer 12

If Km were to be 0, there will be no flux and the drugs will have to be absorbed through aqueous pores (channels) or transporters.

Question 13

Function of P-glycoprotein

Answer 13

• present throughout the body
• acts as reverse pump generally INHIBITING absorption
• active, ATP-dependent process

Question 14

Characteristics molecules must have to travel through aqeuous pores

Answer 14

• less than 180 Da
• lipid solubility doesn’t matter
• can be charged
• Fick’s law doesnt hold true

Question 15

Characteristics for a molecule to travel paracellularly

Answer 15

• less than 350 Da
• ipid solubility doesn’t matter
• can be charged
• Fick’s law doesnt hold true

Question 16

Characteristics of molecules that travel transcellularly

Answer 16

• greater than 350 Da
• lipid solubility is important
• Fick’s law applies

Question 17

true or false: to cross the cell membrane, the drug molecules should be in solution.

Answer 17

True

Question 18

Why is a balance in hydrophilicity required?

Answer 18

If a drug is very hydrophilic, the membrane permeability will be limited and if a drug is very hydrophobic, the water solubility will be limited and there will be less concentration gradient for diffusion.

Question 19

Drug A has very low lipid solubility but has 90% oral bioavailability. What is the possible reason for this high bioavailability?
a) high aqueous solubility
b) low molecular weight (<180 Da)
c) P-glycoprotein
d) both B and C

Answer 19

B