L13 - Optimising Drug Properties for Oral Bioavailability

• Requirements for a "good drug"

  - Effective target interactions- suitable shape/size/chemical composition - good chemical stability- favorable hydrophobic/hydrophilic characteristics- good aqueous solubility- good oral bioavailability
• Oral bioavailability


  the amount of drug that reaches its target and the rate of absorption
• Lipophilicity(what is it? What is it described by?)

  how lipid soluble a drug is. (chemical attraction of a substance to lipids)Described as log P. As log P increases, lipophilicity increases.

  
• Drug lipophilicity(what does it affect? why is a balance required? why are polar functional groups needed?)


  - Affects absorption, distribution, and elimination-Must be lipophilic to cross cell membranes BUT too much lipophilicity may lead to deposition in fatty tissue- polar functional groups needed for binding to receptors/enzymes via H bonds
• Octanol-water partition coefficient (P)(what is it? what does it measure? what's the eqn?)


  - parameter measuring drug lipophilicity= ratio of lipid solubility to water solubilityP = [drug] oct / [drug] water

  
• Determination of log P(how do we measure log p? what's the optimum?)

  - add known mass of drug to equal volumes of H2O and Octanol- Mix; allow oil and water phase to separate- measure [drug] in each phaselog P = log [drug] oil / [drug] wateroptimum = log P 1-5

  
• Lipinski's Rule-of-5

  Qualitative consideration of oral bioavailability prediction1 - Mr < 5002 - log P < 53 - max 5 H bond donors4 - max. 10 H bond acceptors (solubility also a factor - higher doses eg 250mg+ may need higher solubilities)

  
• Testing the Rule-of-5: aspirin(Molecular weight = 180.1, log P = 1.19, H-bond acceptors = 4, H-bond donors = 1, water solubility = 4.6 mg/mL)

  Yes - good oral bioavailability
• Testing the Rule-of-5: propranolol(Molecular weight = 259.3, log P = 2.60, H-bond acceptors = 3, H-bond donors = 2)

  Yes - good oral bioavailability
• Testing the Rule-of-5: Taxol(Molecular weight = 853.9, log P = 7.4, H-bond acceptors = 15, H-bond donors = 4)


  No - not good oral bioavailability (Mr too big to diffuse across membrane. BUT formulated via IV route not oral, so still a good drug)
• Rule-of-5 comparisons(how can oral bioavailability problems be solved?)

  - Drugs that don't satisfy Lipinski's rules can still be good drugs- by changing formulation or route of delivery eg via IV- drug can be modified to alter polarity and log P