L13 - Optimising Drug Properties To Ensure Good Oral Bioavailability

Question 1

What are requirements for a good drug?

Answer 1

• efficacy
• chemical stability
• solubility
• Suitable LogP value (1-3)
• oral bioavailability
• appropriate pharmacokinetics
• favourable safety profile

Question 2

When is a drug highly active in vitro of no use?

Answer 2

• if it can’t be absorbed
• if it has poor in vivo performance

Question 3

What is a key parameter of physiochemical in drug development?

Answer 3

Lipophilicity

Question 4

What happens when a drug is too hydrophilic?

Answer 4

• good solubility
• poor partitioning in the cell membrane

Question 5

What happens when a drug has enough lipholic character?

Answer 5

Partitions into cell membrane and out

Question 6

What happens when a drug is too lipophilic?

Answer 6

• poor solubility
• struggles to partition out of the membrane
• can accumulate in fatty tissues

Question 7

What factors affect LogP and lipophilicity?

Answer 7

• chemical structure of a drug
  = ionisation
  = hydrogen bonding

Question 8

What does a drug need to have for optimal absorption?

Answer 8

Suitable balance of solubility and lipophilicity

Question 9

What is the effect of pH on oral drug absorption?

Answer 9

Small drugs tend to be WB or WA
= ionisation changes with varying pH
- affects the lipophilicity

Question 10

What are ionised drugs like vs un-ionised form?

Answer 10

• increased hydrophilicity
• reduced membrane permeability

Question 11

What are un-ionised drugs like vs ionised form?

Answer 11

• increased lipophilicty
• optimal membrane permeability

Question 12

What type of acids and bases are poorly absorbed?

Answer 12

SA and SB

Question 13

What is the pH partition hypothesis?

Answer 13

Drug accumulates on the side of the membrane where pH favours ionisation

Question 14

What does the pH partition hypothesis not take into account?

Answer 14

• type of epithelium
• SA of absorption site
• ionised drugs absorbed to a smakk extent
• active transport of drugs
• residence time of drug at delivery site
• charged drugs may form ion pairs

Question 15

What is LogD?

Answer 15

An alternative measure of lipophilicty that is more realistic
- takes charged species into account

Question 16

When is a drug more lipophilic in terms of LogD?

Answer 16

The higher the value of LogD

Question 17

What happens in de-solvation in terms of H bonds?

Answer 17

They must be broken before a drug in solution can enter the lipid plasma membrane

Question 18

What is Lipinski”s rule of 5?

Answer 18

Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings

Question 19

What drug properties are investigated by Ro5?

Answer 19

• lipophilicity - LogP
• size - MW
• H bonding - num of donors and acceptors

Question 20

What are the criteria that the Ro5 states a drug needs to follow foor good oral absorption?

Answer 20

• MW <= 500
• Log P <= 5
• H-bond donors (OH + NH) <= 5
• H bond acceptors (N+O) <= 10

Question 21

What diffusion does the Ro5 criteria apply to? What are the exceptions?

Answer 21

• applied to passive, transcellular diffusion
• except drugs which are substrates of uptake transporters

Question 22

What substances don’t comply with the Ro5?

Answer 22

Antibiotics
- natural compounds or semi-synthetic

Vitamins, cardiac glycosides, antifungals

Question 23

What is Ro5 also useful for?

Answer 23

Assesing the likelihood of a drug being well absorbed following oral delivery

Question 24

What is an alternative to the Ro5?

Answer 24

Veber’s rules
- num of rotatable bonds <= 10
- total polar SA (TPSA) <= 140 A^2
- total H bond count <= 12

Question 25

What if a drug which has excellent activity in vitro has poor oral bioavailability?

Answer 25

Chemical modification to alter polarity or LogP assuming it doesn’t affect binding to target

Question 26

What chemical modifications can be done to alter biovailability?

Answer 26

• add ionisable groups ^ solubility
• change pKa functional groups ^ lipophilicity
• reduce num of H bond donors/acceptors
• pro-drug strategies

Question 27

What happens to oral absorption when a drug is too hydrophilic?

Answer 27

Limited due to limited permeability

Question 28

How can you improve lipophilicity and membrane permeability?

Answer 28

Chemically modify with lipophilic groups

Question 29

What is the pro-drug approach?

Answer 29

Metabolic processes within cells cleave the lipophilic groups to release the active drug