Prodrugs

Question 1

What is a prodrug? What are the types? What are the methods of activation?

Answer 1

compounds which require metabolic transformation before exhibiting a biological response
- simvastatin, omeprazole, aciclovir, enalapril

Question 2

Why were prodrugs designed?

Answer 2

to manipulate specific properties
- physicochemical, pharmacokinetic, pharmacodynamic

to overcome pharmaceutical, pharmacokinetic, or pharmacodynamic barriers
- chemical stability, poor solubility
- blood-brain barrier permeability, pre-systemic metabolism
- taste or odour, irritation or pain, oral absorption

can target specific tissue or cell type

Question 3

What are applications of prodrugs?

Answer 3

Improved solubility

Enhance drug absorption
- modify lipophilicity and drug transport

Sustained release
Site-specific delivery
Improved taste
Improved stability

Question 4

How can solubility be improved? Why does it need to be improved?

Answer 4

solubility can be improved by
- addition of charged promoieties
= phosphates, hemisuccinates (chloramphenicol)

• addition of neutral promoieties
  = high mW PEGs

solubility needs to be improved because poor solubility can be a limiting factor for iv, sc, percutaneous and oral bioavailability

e.g.
fosphenytoin is a hydrophilic phosphate prodrug of phenytoin, which is poorly soluble
- is hydrolysed rapidly by phosphatases
= this assists iv bioavailability

Question 5

How is drug absorption improved? Why should cautions be taken?

Answer 5

improve passive transport
- via enhanced lipophilicity
e.g. ACE inhibitors, simvastatin, pivampicillin

esters of carboxylic acids can be cleaved by hydrolysis (enzymatic or chemical) to active carboxylic acid

cautions
- reduction in solubility will lead to dissolution rate
limited absorption and hence may affect bioavailability
- toxicity of pro moiety must be evaluated or existing approved ones used

Question 6

Why are slow/sustained release prodrugs used?

Answer 6

Protection against fast metabolic breakdown

Increased chemical or metabolic stability

For oral or parenteral routes
- steroid esters in oily vehicles for IM injection

e.g. flupenthixol

Question 7

What are the benefits of slow/sustained release prodrugs (flupenthixol)?

Answer 7

Reduce number and frequency of doses
Reduce peak and trough effects
Reduction in toxicity
Reduce overall dosage required
Eliminates night-time administration
Improved patient compliance

Question 8

How is transporter mediated intestinal absorption improved? What is an example?

Answer 8

Target oligopeptide transporter
- increases bioavailability

Valaciclovir
- substrate for intestinal PEPT1 transporter
- 5x higher oral bioavailability

Question 9

How is taste improved? What is a disadvantage of improving taste?

Answer 9

taste masking
- solubility suppression

e.g. clindamycin

disadvantage
- reduced solubility and increased first pass metabolism

Question 10

How can stability be improved?

Answer 10

Degradation depends on the fraction in liquid phase i.e. amount available for reaction

Lower storage temperature – slower degradation

Increase melting point of drug – slower degradation

Question 11

What is a possible issue associated with prodrugs of highly charged drugs?

Answer 11

intracellular release may result in entrapment, toxicity or unpredictable metabolism

Question 12

What are the types of prodrugs? How are they classed?

Answer 12

Chemical classes
- e.g. site-specific chemical delivery systems, carrier-linked, drug-antibody conjugates

Mechanism of activation
- e.g. enzymatic, non-enzymatic, hydrolysis, oxidation, reduction