Lec 10-Drug delivery drug carries and targeting

Question 1

Barriers to oral drug delivery

Answer 1

• GIT- Dissolution: Degradation; pH; Enzymes
• Mucus- Diffusion: Binding; Electrostatic repulsion (mucus is negatively charged)
  
  • Positive drugs chelate= inactive, negative drugs= repelled
• Epithelium- Membrane transport: Diffusion; enzymes; brush-border

Question 2

Drug absorption

Answer 2

• The epithelial lining presents a barrier to drug absorption
• Epithelia are classified based on their shape, number of cells that form an epithelial barrier and their specialisation
• Mucus secreted from goblet cells presents an additional barrier to drug absorption

Question 3

Barriers to drug absorption

Answer 3

• Epithelia are tissue composed of one or more layers of cells
• These layers are supported by a basement membrane which lies on top of the supporting connective tissue
• Their function includes absorption, secretion and protection and is dependent on their location within the body

Question 4

The shapes of epithelial cells

Answer 4

• Squamous- these cells have a flat (squashed) shape
• Columnar- these are narrow, tall cells
• Cuboidal- these cells have a cubic shape, intermediate between squamous and columnar

Question 5

Stratification (number of cell layers) of epithelial

Answer 5

• Simple- single layer of cells, termed epithelium
• Stratified- multiple layers

Question 6

Specialisation- some epithelia will have a specialised function

Answer 6

• Kerantinized cells contain keratin protein to improve strength of the barrier
• Ciliated cells have apical membrane extensions that can increase the overall absorption area and rhythmically beat to move mucus
• Must also consider tight junctions, more tight junctions will reduce absorption of drugs

Question 7

Mechanisms of drug absorption across epithelia

Answer 7

• Paracellular diffusion (between cells) drugs must be hydrophilic as the medium between cells is mostly water
• Transcellular diffusion (through the cells) drugs must be lipophilic to pass over the phospholipid bilayer
• Endocytosis- binds to a receptor
• P-gp causes drugs to be removed from the cells

Question 8

Transport processes

Answer 8

• Transcellular
  
  • Passive diffusion- based on a concentration gradient (only lipophillic)
  • Carrier-mediated- based on a carrier
  • Endo-cytosis- swollow drug into cell through receptor binding
• Paracellular- based on a concentration gradient
• Efflux

Question 9

Passive diffusion transcellular

Answer 9

• Transport through cells
• No energy put into the system
• The rate usually determined by diffusion across the lipid bilayer of the cell membrane- from high to low concentration
• Lipophilicity is important, and an optimum logP is usually observed
• If the drug is hydrophilic drug can’t cross the bilayer
• If the drug is too lipophillic, the drug will not want to exit the cell into the blood stream

Question 10

Transport mechanisms transcellular- passive

Answer 10

• Rate of transport across a membrane is dependent on
  
  • Concentration gradient
  • Diffusion co-efficient
  • Partition co-efficient
  • Area of contact

Question 11

Factors controlling passive absorption

Answer 11

• Drug concentration
• Partition co-efficient
• Area of absorptive tissue

Question 12

Modelling of absorption

Answer 12

• Don’t need to memorise
• Smaller molecules are easier to pass through a membrane than larger ones

Question 13

Transcellular

Carrier-mediated processes

Answer 13

• Involvement of specific proteins in membranes
• Molecules which are similar to the natural substrate are also transported (Analogues)
• But dissimilar ones are not transported
• E.g. large neutral amino acid carrier system
• Require energy- operate against the concentration gradient
• Have specific stereochemical requirements
• May require associated ions (Na+/H+)
• Saturable at higher conc
• Uptake can be initiated by competitors

Question 14

Carrier-mediated transport

Effect of Kd

Answer 14

Question 15

Transcytosis

Answer 15

• Internalisation- by engulfment by the cell membrane
• Receptor-mediated endocytosis
  
  • Interaction with specific surface receptors
  • Saturable
• Adsorptive endocytosis
  
  • Non-specific interaction with cell surface
  • Non-saturable
• Pinocytosis
  
  • Continuous cell drinking- to sample environment

Question 16

Endocytosis: receptor-mediated

Answer 16

• Binding to surface receptors which contact with adaptins
• Complexes migrate laterally in membrane clathrin-mediated
• Invagination and vesicle formation
• Loss of clathrin coat
• Loss of adapting
• Fusion with early endosomes pH-falls
• Endosome delivers contents as programmed e.g. lysosome, opposite membrane
  
  • Receptor returns to the membrane

Question 17

Pinocytosis

Answer 17

• Cell samples environment (drinking) and internalises molecules in bathing fluid

Question 18

Paracellular route

Answer 18

• Drugs can also cross epithelia through gaps (Known as gap junctions) between cells
• Governed by passive diffusion and small hydrophillic molecules can pass through these gap junction

Question 19

Paracellular transport effect of molecular size

Question 20

Efflux from cells p-Glycoprotein

Answer 20

• Encoded by MDR1
• Apical transmembrane protein- MR ~170kDa
• Efflux of many drugs from within cells
  
  • E.g. cytotoxics- total, vinca alkaloids
  • E.g. other- steroids, immunosuppressants, antibiotics
• Wide range of substrates
  
  • MR 300-2000
  • Polarity
    
    • Substrate- more hydrophilic hydrocortisone
    • Non-substrate- more hydrophobic progesterone

Question 21

Mechanism dependent upon physicochemical properties

Answer 21

Question 22

What you should be able to do

Answer 22

• Indentify the essential features of
  
  • Transcellular absorption via
    
    • Passive diffusion
    • Carrier-mediated transport
    • Transcytosis
  • Paracellular absorption
  • Eflux
• Provide named examples of each- and relate processes to the physicochemical/structural feature of the molecule