Prodrugs

Question 1

What is a prodrug?

Answer 1

A compound which requires metabolic transformation before exhibiting a biological response
i.e. Simvastatin, Omeprazole, Aciclovir, Enalapril

Question 2

Reasons for a prodrug

Answer 2

To manipulate specific properties
To over come pharmaceutical, pharmacodynamic, pharmacokinetic properties i.e. chemical stability, poor solubility, taste, odour, oral absorption, blood brain barrier
Target specific tissue or cell type

Question 3

Improved solubility

Answer 3

Poor solubility is a limiting factor
Charged promoieties – phosphates (phosphatase), hemisuccinates (esterases)
Neutral promoieies – High MW PEG’s

Question 4

Improved passive transport

Answer 4

Enhanced lipophilicity for transport
Esters of carboxylic acids cleaved by hydrolysis to active carboxylic acids
i.e. ACE inhibitors, Simvastatin
Needs to be a balance between lipophilicity and solubility as reduction in solubility will lead to dissolution rate limited absorption and may reduce bioavailability

Question 5

Slow release prodrugs

Answer 5

Protection against fast metabolic breakdown

Question 6

Improved transported mediated intestinal absorption

Answer 6

Target oligopeptide transporter
Potential drug-drug interactions due to saturation/inhibition of transporter
Enalapril, β lactam antibiotics, Valaciclovir

Valaciclovir is a substrate for intestinal PEPT1 transporter

Question 7

Improved taste

Answer 7

Decreasing the solubility masks the taste

Question 8

Melting point effects

Answer 8

Degradation occurs in liquid phase
Lowering storage temperatures causes slower degradation
Increasing melting point causes slower degradation