Optimising drug properties to ensure good oral bioavailability

Question 1

Important considerations in drug design

Answer 1

Requirements for a ‘good drug’
* Effective target interactions
* Suitable shape/size/chemical composition
* Good chemical stability
* Favourable hydrophobic/hydrophilic characteristics (log P = 1-3)
* Aqueous solubility
* Oral bioavailability
* Pharmacokinetics
Compounds with the best target binding interactions may fail as drugs due to poor in vivo properties or metabolic reactions within the body.

Question 2

Drug lipophilicity – log P

Answer 2

• A drug’s lipophilicity affects its absorption, distribution and elimination.
• Drugs must be lipophilic to cross cell membranes, but…
  
  • if they are too lipophilic they may be deposited in fatty tissue.
• Polar functional groups are needed to bind to receptors/enzymes (H-bonds).
  The octanol-water partition coefficient (P) is a physicochemical parameter that measures drug lipophilicity

Question 3

The octanol-water partition coefficient (P) is a physicochemical parameter that measures drug lipophilicity, and is defined:

Question 4

Determination of log P

Answer 4

• Equal volumes of water and octanol
• Known mass of drug
• Mix thoroughly
• Allow two phases to separate
• Measure the concentration of drug in each phase
• log P values can be predicted in silico
• Values obtained computationally are known as clog P
  
  • calculated log P

Question 5

Lipinski’s Rule-of-5

Answer 5

Qualitative rule of thumb, often used in pharmaceutical science because it works very well!
* Considers physiochemical properties of a drug candidate in terms of potential bioavailability.
* The rule predicts that good oral bioavailability (i.e., suitable drug concentration in circulation following oral administration) is likely when:
* Molecular weight ≤ 500
* log P ≤ 5
* No more than 5 hydrogen bond donors
* No more than 10 hydrogen bond acceptors
* All units are multiples of five

Optimum drug log P is usually in the range 1-3
* log P is carefully considered in drug design to ensure optimum lipophilicity

if the log p is to high it can be injected by IV straight into body

Question 6

Lipinski is not an ‘absolute’

Answer 6

Nota bene: the Rule of Five is strictly qualitative
Most drugs (>80%) satisfy the Rule-of-5
Those that do not, however, are not necessarily poor drugs
Bioavailability problems can be solved by formulation or by an alternative route of delivery, or a drug may be chemically modified to alter its polarity and log P