L13 - Optimising Drug Properties To Ensure Good Oral Bioavailability Flashcards
What are requirements for a good drug? (7)
- efficacy
- chemical stability
- solubility
- Suitable LogP value (1-3)
- oral bioavailability
- appropriate pharmacokinetics
- favourable safety profile
When is a drug highly active in vitro of no use? (2)
- if it can’t be absorbed
- if it has poor in vivo performance
What is a key parameter of physiochemical in drug development?
Lipophilicity
What happens when a drug is too hydrophilic? (2)
- good solubility
- poor partitioning in the cell membrane
What happens when a drug has enough lipholic character?
Partitions into cell membrane and out
What happens when a drug is too lipophilic? (3)
- poor solubility
- struggles to partition out of the membrane
- can accumulate in fatty tissues
What factors affect LogP and lipophilicity?
- chemical structure of a drug
= ionisation
= hydrogen bonding
What does a drug need to have for optimal absorption?
Suitable balance of solubility and lipophilicity
What is the effect of pH on oral drug absorption?
Small drugs tend to be WB or WA
= ionisation changes with varying pH
- affects the lipophilicity
What are ionised drugs like vs un-ionised form?
- increased hydrophilicity
- reduced membrane permeability
What are un-ionised drugs like vs ionised form?
- increased lipophilicty
- optimal membrane permeability
What type of acids and bases are poorly absorbed?
SA and SB
What is the pH partition hypothesis?
Drug accumulates on the side of the membrane where pH favours ionisation
What does the pH partition hypothesis not take into account? (6)
- 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
What is LogD?
An alternative measure of lipophilicty that is more realistic
- takes charged species into account
When is a drug more lipophilic in terms of LogD?
The higher the value of LogD
What happens in de-solvation in terms of H bonds?
They must be broken before a drug in solution can enter the lipid plasma membrane
What is Lipinski”s rule of 5?
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
What drug properties are investigated by Ro5?
- lipophilicity - LogP
- size - MW
- H bonding - num of donors and acceptors
What are the criteria that the Ro5 states a drug needs to follow foor good oral absorption?
- MW <= 500
- Log P <= 5
- H-bond donors (OH + NH) <= 5
- H bond acceptors (N+O) <= 10
What diffusion does the Ro5 criteria apply to? What are the exceptions?
- applied to passive, transcellular diffusion
- except drugs which are substrates of uptake transporters
What substances don’t comply with the Ro5?
Antibiotics
- natural compounds or semi-synthetic
Vitamins, cardiac glycosides, antifungals
What is Ro5 also useful for?
Assesing the likelihood of a drug being well absorbed following oral delivery
What is an alternative to the Ro5?
Veber’s rules
- num of rotatable bonds <= 10
- total polar SA (TPSA) <= 140 A^2
- total H bond count <= 12
What if a drug which has excellent activity in vitro has poor oral bioavailability?
Chemical modification to alter polarity or LogP assuming it doesn’t affect binding to target
What chemical modifications can be done to alter biovailability? (4)
- add ionisable groups ^ solubility
- change pKa functional groups ^ lipophilicity
- reduce num of H bond donors/acceptors
- pro-drug strategies
What happens to oral absorption when a drug is too hydrophilic?
Limited due to limited permeability
How can you improve lipophilicity and membrane permeability?
Chemically modify with lipophilic groups
What is the pro-drug approach?
Metabolic processes within cells cleave the lipophilic groups to release the active drug
