LADMER and Polarized Epithelium

Question 1

What is the LADMER system?

Answer 1

liberation
-drug in dosage form dissolves in solution
absorption
-IM, SC, nasal, etc already absorbed (no dissolution)
-free drug encounters enzymes/transporters in GIT and liver (presystemic circulation)
distribution
-free drug can: bind with proteins, enter biophase, cross tissue and be eliminated
elimination
-metabolism and excretion
response
-drug bound to receptor produces a response (therapeutic, subtherapeutic, adverse, toxic)

Question 2

True or false: presystemic circulation is part of Cls

Answer 2

false
Cls only encompasses clearance from the systemic circulation

Question 3

What determines drug response?

Answer 3

LADME
-dose and LADME determines Cp
-Cp relates to clinical response

Question 4

What is the nature of cell membranes?

Answer 4

semipermeable
phospholipid bilayer
proteins on the outside
selective barrier

Question 5

What is the polarized epithelium?

Answer 5

single layer of epithelial cells that are held together by tight junctions
-tight junctions result in polarization of epithelium

Question 6

What are the mechanisms for transport across the polarized epithelium?

Answer 6

transcellular (major way, across cells)
-passive diffusion
-endo/exocytosis
-carrier mediated (active, facilitated diffusion)
paracellular (between cells)
-tight junctions prevent drug transport

Question 7

How do we describe passive diffusion?

Answer 7

Ficks Law
dq/dt=PA(C1-C2)

Question 8

How does LADME determine drug response?

Answer 8

LADME and dose determines Cp
Cp relates to clinical response

Question 9

How is P (membrane permeability coefficient) determined?

Answer 9

P=K x D/h
k: partition coefficient
D: diffusion coefficient within membrane
h: membrane thickness

Question 10

What is rate of diffusion proportional to?

Answer 10

concentration gradient

Question 11

What are the physicochemical properties of the drug that can impact diffusion capacity?

Answer 11

molecular size: small>large
lipophilicity: lipid>polar
H-bonding: less
ionization: unionized>ionized
protein binding: unbound>bound

Question 12

What is the true partition coefficient, K?

Answer 12

indicates water to lipid solubility
constant for unionized drug: pH has no effect

Question 13

What influences permeability coefficient (P)?

Answer 13

physicochemical properties of drug

Question 14

What does an elevated K tell us?

Answer 14

increased lipid solubility and increased ability to traverse membrane

Question 15

How is K determined?

Answer 15

[HA]octanol/[Ha]water

Question 16

What is the relationship of ionization to apparent partition coefficient for acidic drugs? What about basic drugs?

Answer 16

acidic drugs:
-as pH increases, K’ decreases=decreased ability of weak acid to cross membrane
basic drugs:
-as pH increases, K’ increases=increased ability of weak base to cross membrane

Question 17

How does the pH partition hypothesis affect the partition coefficient, K?

Answer 17

drug accumulates most on side of membrane where pH favours ionization

Question 18

Describe the rate of transport for carrier-mediated diffusion and passive diffusion as drug concentration increases.

Answer 18

carrier-mediated:
-increases and then plateaus
-proteins are saturated
-rate is greater than diffusion
passive diffusion:
-rate of transport is proportional to Cp
when transporters are involved, rate of diffusion is much greater than passive diffusion

Question 19

What are the two major families of drug transporters?

Answer 19

solute carrier family (SLC, SLCO)
-uptake or bidirectional
ATP binding cassette family (ABC)

Question 20

What is K’?

Answer 20

apparent partition coefficient
-index of comparative solubilities
-accounts for ionization in aqueous
-affected by pH and pKa
takes into consideration degree of ionization of drugs in the physiological system, thus a better measure of lipophilicity than K