Optimising Drug Properties to Ensure Good Oral Bioavailability

What is oral bioavailability?

The fraction of an orally administered drug that reaches systemic circulation unchanged.

Why can a highly active drug be useless clinically?

• They not be absorbable

• Highly active drugs are rapidly metabolised

• High active drugs too toxic in vivo.

What key properties are required for a good drug?

Efficacy

Suitable size/structure

Chemical stability

Solubility

Suitable lipophilicity (LogP ~1–3)

Appropriate pharmacokinetics

Safety

What is LogP?

The log10 of a drug’s partition coefficient between octanol and water; a measure of lipophilicity.

Why is LogP important for oral absorption?

It reflects a drug’s ability to partition into lipid membranes and cross the gut epithelium.

Why is very low LogP bad?

Drug is too hydrophilic → poor membrane permeability.

Why is very high LogP bad?

Poor aqueous solubility, poor exit from membranes, and possible accumulation in fatty tissue.

What factors influence lipophilicity?

Chemical structure, ionisation, and hydrogen bonding.

How does ionisation affect absorption?

• Ionised = more hydrophilic → poorer membrane permeability

• Unionised = more lipophilic → better membrane permeability

Why are most drugs weak acids or weak bases?

So their ionisation (and absorption) can change with physiological pH.

Why are strong acids (pKa <3) and strong bases (pKa >10) poorly absorbed?

They are almost completely ionised in the intestine → low permeability.

What is the pH partition hypothesis?

Drugs accumulate on the side of a membrane where pH favours their ionised form, but cross membranes mainly in the unionised form.

Which form crosses membranes best?

Unionised (lipophilic) form.

Why is the pH partition hypothesis limited?

It ignores epithelium type, surface area, active transport, residence time, and ion pairing.

Based only on pH partition, where would weak acids be best absorbed?

In acidic environments (e.g., stomach) where they are more unionised.

In reality, where does most absorption occur?

Small intestine, due to huge surface area and long residence time.

Why does hydrogen bonding reduce absorption?

H-bonds must be broken (desolvation) before a drug can enter the lipid membrane, costing energy.

What is Lipinski’s Rule of Five used for? What are the rules?

Predicting the likelihood of good oral absorption.

• MW ≤ 500

• LogP ≤ 5

• H-bond donors ≤ 5

• H-bond acceptors ≤ 10

When is poor absorption likely according to Ro5?

If two or more of the rules are broken.

What type of absorption does Ro5 mainly apply to?

Passive transcellular diffusion.

Which types of drugs often break Ro5 but are still used orally?

Antibiotics, natural products, vitamins, cardiac glycosides, antifungals.

What are Veber’s rules?

• Rotatable bonds ≤ 10

• TPSA ≤ 140 Ų or total H-bond count ≤ 12

Why are rotatable bonds and TPSA important?

They influence molecular flexibility and polarity, which affect permeability.

How can poor oral bioavailability be improved chemically?

• Add/remove ionisable groups

• Adjust pKa

• Reduce H-bond donors/acceptors

• Use pro-drug strategies

What is a pro-drug?

An inactive or less active compound converted in the body into the active drug.

Why are pro-drugs used?

To improve lipophilicity, permeability, stability, or absorption.

Give one example of pro-drug benefit.

Increasing lipophilicity improves membrane permeability and oral bioavailability.

What non-chemical methods can improve absorption?

Permeation enhancers, formulation changes, increasing residence time, inhibiting efflux pumps, nanomedicine.

Why must a drug dissolve before absorption?

Only drug in solution can diffuse to and across membranes.

What balance is needed for good oral absorption?

Enough solubility to dissolve + enough lipophilicity to cross membranes.