Unit 2 - Biological barriers & ADME 1

Question 1

Give five ways of transport across a biological barrier

Answer 1

Passive transcellular
Passive paracellular
Vesicular
Efflux
Metabolism

Question 2

What are tight junctions made from?

Answer 2

Proteins between two cells forming non-covalent bonds

Question 3

What is passive transport limited by?

Answer 3

Availability of an electrochemical gradient and suitable drug physiochemical properties for permeability

Question 4

What are solute carriers limited by?

Answer 4

Selectivity of transporter for chemical features of substrate and availability of electrochemical gradient

Question 5

What are active efflux carriers limited by?

Answer 5

Selectivity of transporter for chemical features of substrate
- driven by primary energy source

Question 6

What is vesicular movement important for?

Answer 6

Limited importance for small molecules
Important for proteins/peptides
- endocytosis
- transcytosis

Question 7

What is metabolism limited by?

Answer 7

Selectivity of enzyme for chemical features of substrate

Question 8

Give examples of types of epithelial barriers

Answer 8

Simple squamous
- lung alveolar type I
Simple cuboidal
- lung alveolar type II
Simple columnar
- kidney proximal tubule
Stratified squamous
- buccal
- non-keratinised
- skin
- keratinised
Stratified cuboidal
- glands and ducts
Stratified columnar
Pseudostratified columnar
- conducting airways of lung
- intestine
- nasal cavitiesSimple squamous
- lung alveolar type I
Simple cuboidal
- lung alveolar type II
Simple columnar
- kidney proximal tubule
Stratified squamous
- buccal
- non-keratinised
- skin
- keratinised
Stratified cuboidal
- glands and ducts
Stratified columnar
Pseudostratified columnar
- conducting airways of lung
- intestine
- nasal cavities

Question 9

Which type of molecules don’t readily partition into cell membranes?

Answer 9

Hydrophilic molecules

Question 10

How do hydrophilic molecules cross epithelial barriers?

Answer 10

Paracellular transport

Question 11

Which type of molecules permeate easily across cell membranes?

Answer 11

Hydrophobic molecules

Question 12

How do hydrophobic molecules cross epithelial barriers?

Answer 12

Transcellular transport

- large surface area

Question 13

Give some examples of types of capillary

Answer 13

Continuous capillaries
Fenestrated capillaries
Discontinuous capillaries

Question 14

How do normal capillaries allow paracellular diffusion of small molecules?

Answer 14

Cell junctions are not tightly sealed

Question 15

Which barrier is the exception to capillary endothelium cells not being tightly sealed?

Answer 15

Blood Brain Barrier

Question 16

What is a continuous capillary?

Answer 16

Epithelial cells that are held together by tight junction with intercellular clefts to allow fluid passage

Question 17

What is a fenestrated capillary?

Answer 17

Perforated by fenestra bearing thin diaphragm

- glomerular capillaries

Question 18

What is a discontinuous capillary also known as?

Answer 18

Sinusoids

Question 19

What is a discontinued capillary?

Answer 19

Contains inter-endothelial gaps >100nm wide
Discontinuities in the basement membrane as well
- liver sinusoids
- movement of macrophages and large particles

Question 20

What molecular properties effect the process of how a molecule will cross a membrane (e.g partitioning, diffusion, stability within barrier)?

Answer 20

Steric; molecular size, volume, shape
Hydrophobicity; lipid/ water
Ionic properties; Hydrogen bonding potential, pKa

Question 21

What is solubility?

Answer 21

Property of a solid to dissolve in a liquid to form a homogenous solution
solubility depends on the:
- physical and chemical properties of the solute
- temperature
- pressure
- pH of solution

Question 22

What is permeability?

Answer 22

Property of a membrane to allow passage of a solute

• permeability depends on the
• physical and chemical properties of the solute
• physical and chemical properties of the membrane
• temperature
• pH of solution

Question 23

What is partition coefficient, P?

Answer 23

Measure of the differential solubility between octanol/water for neutral compounds or where the compound exists in a single form

Question 24

What is partition coefficient, D?

Answer 24

Appropriate descriptor for ionisable compounds as it is a measure of the pH dependent differential solubility of all species in the octanol/water system

Question 25

What is LogD dependent on for ionisable compounds?

Answer 25

pH and pKa | - distribution of charged and uncharged forms will change

Question 26

What are the two types of superfamilies of transporters present in cell membranes?

Answer 26

``` ATP-dependent Binding Cassette (ABC) binding proteins Solute carriers (SLC) ```

Question 27

Give some examples of ATP-dependent Binding Cassette (ABC) binding proteins

Answer 27

``` P-glycoprotein - P-gp Multidrug Resistant Proteins - MRPs Breast Cancer Resistance Protein - BCRP ```

Question 28

Give some examples of Solute Carriers (SLC)

Answer 28

``` Organic cation transporters - OCTs Organic cation/carnitine transporters - OCTNs Organic anion transporters - OATs Organic anion transporting polypeptides - OATPs Peptide transporters - PEPT1 - PEPT2 Amino acid transporters Monocarboxylate transporters ```

Question 29

google pka and ionisaion

Answer 29

ghg

Question 30

Where does P-glycoprotein expression increase in the apical (luminal) plasma membrane of small intestine enterocytes?

Answer 30

From proximal to distal regions of the small intestine

Question 31

What factors affect the impact of P-glycoprotein?

Answer 31

P-gp expression and affinity for a drug - higher pull through membrane Passive membrane flux - bypass P-gp

Question 32

Where is P-glycoprotein constitutively expressed?

Answer 32

Blood Brain Barrier Lung epithelium Kidney Liver

Question 33

Give some examples of where integral membrane proteins found

Answer 33

Plasma membrane Mitochondria Intracellular organelles

Question 34

What is a secondary active transporter?

Answer 34

Transporter protein couples the movement of an ion (typically Na+ or H+) down its electrochemical gradient to the uphill movement of another molecule or ion against a concentration/electrochemical gradient

Question 35

What is a symport carrier?

Answer 35

A cotransporter carrying 2 molecules in the same direction (either into or out of the cell)

Question 36

What is an antiport carrier?

Answer 36

A cotransporter carrying 2 molecules in different directions