L3 Drug Absorption

Question 1

Drug Absorption

Answer 1

process by which a drug moves from its site of administration to the systemic circulation.

Question 2

Explain what it means that the body is compartmentalised

Answer 2

drugs need to cross lipid membrane to move from one compartment
to another compartment

Question 3

Transcellular

Answer 3

Move across a cell
- lipophilic
- passic diffusion/facilitation diffusion/active

Question 4

Paracellular

Answer 4

Through tight junction
- low molecular weight and hydrophilic

Question 5

Administration routes

Answer 5

Oral and Intravenous (veins)

Question 6

Factors affecting oral absorption
i and ii and iii

Answer 6

i- Molecular Size
>oral absorption decreases as molecular weight ↑
ii- Solubility
>hydrophilicity and lipophilicity affect passive diffusion at membranes
iii- Ionisation

Question 7

Two ways to estimate drug solubility

Answer 7

LogP - partition coefficient
Polar surface area and topological psa

Question 8

LogP

Answer 8

Two layer solvents - organic and water then add drug and mix then allow layers to equilibrate. Then you measure drug concentration in both layers.
If more in solvent then lipophilic/ if more in water then hydrophilic

Question 9

logP Values of oral drugs

Answer 9

less than 5

Question 10

Prodrugs

Answer 10

medications that turn into an active form once they enter the body.

Question 11

PSA

Answer 11

Polar surface area
sum of surface of polar atoms (N/O) in a molecule and attached to H

Question 12

PSA predict

Answer 12

Intestinal absorption and blood-brain barrier crossing

Question 13

Topological PSA

Answer 13

Calc the sum of tabulated surface contributions of polar fragments (computational method)

Question 14

Factor affect oral - ionisation and pH dependant ionisation

Answer 14

many drugs classified as weak acids and based

pH-dependent ionisation of functional groups
- pKa is the pH at which drug molecules are 50% ionised
- only unionised drug molecules can diffuse passively across lipid membranes

Question 15

Lipinski rule (not really important)

Answer 15

< 5 H-bond donors (-OH and -NH)
< 10 H-bond acceptors (-O and -N)
molecular weight < 500
the calculated logP < 5

Question 16

Biological factors that affect oral absorption

Answer 16

• pH
• ingested food
• gut mobility
• intestinal enzymes
• transporters

Question 17

Early detection of aspirin overdose treated with activated charcoal to decrease aspirin absorption. Why?

Answer 17

Charcoal has pores that allow drug molecules to be attached to activated charcoal. AC is not absorbed and will be excreted or removed through faeces -> decreasing absorption of aspirin

Question 18

Transporters in

Answer 18

Intestine (absorb)
Liver (metabolise)
Kidney (excretion)
or
Organs with barrier function
- brain - placenta

Question 19

Placenta transporters-whatdo they do

Answer 19

protect fetus or developing embryo from harmful symbiotic like alcohol

Question 20

MDR1

Answer 20

(multidrug resistance protein 1) or P-gp (P-glycoprotein)

Question 21

MRP2

Answer 21

(multidrug resistance-associated protein 2)

Question 22

BCRP

Answer 22

(breast cancer resistance protein)

Question 23

3 types of ATP binding cassette transporters

Answer 23

MDR1
MRP2
BCRP

Question 24

In Vitro predict oral absorption with which cells

Answer 24

Caco-2 cells

Question 25

Caco-2 Cells

Answer 25

• og derived from a human colon adenocarcinoma
• an in vitro system to predict intestinal permeability and efflux liability
• grow as a monolayer and differentiate on reaching confluence into intestinal epithelial cells
• express multiple key drug transporters, including MDR1, BCRP and MRP2

Question 26

Apical membrane

Answer 26

the surface of an epithelial cell that faces a lumen, such as that of the intestines

Question 27

Basolateral Membrane

Answer 27

faces the interstitial fluid and is indirectly in contact with the blood

Question 28

Bidirectional Transport Assays

Answer 28

2 ways through the apical chamber or basolateral chamber

A: add drug to A chamber > measure drug conc by taking sample from B chamber at defined time points > calc apparent permeability P (app(A-B))

B: add drug to B chamber > measure drug conc by taking sample from A chamber at defined time points > calc apparent permeability P(app(B-A))

Question 29

Impact on oral bioavailability of a drug

Answer 29

(i) transporter knockout (KO) Caco-2 cell lines
(ii) cells transfected with transporter of interest
(iii) inhibitor of transporter of interest
check slides

Question 30

• drug-drug interaction (DDI)

Answer 30

co-administration of drugs that act as a substrate/an inhibitor/an inducer of efflux transporters