Prodrugs

Question 1

What are prodrugs

Answer 1

• Compounds, which undergo biotransformation before exhibiting a biological response

Question 2

Introduction prodrug

Prontosil a historical example

Answer 2

• Prontosil was a dye that was accidentally found to be antimicrobial
• Prontosil is a dro drug
• Forms sulphanilamide

Question 3

Prontosil

Answer 3

• Diazo- compound, organic dye
• Enzyme, reductase
• Discovery of sulfonamides, first class of antibacterials
• Discovery of drug by chance

Question 4

Design concepts

How to design a prodrug

Answer 4

• Identify: formulation or delivery problems (toxicity, absorption, stability)
• Chemical design:
  
  • A reactive handle on the drug molecule available
    
    • Usually OH, COOH, NH to derivatise to form amide or ester bond
  • Derivatise the drug, form ester e.g.
    
    • To produce appropriate molecular properties
    • Usually with alcohol (for COOH) or carboxylic acid (OH)
  • Ensure activation in the body (to get back the original active drug)
    
    • Degradation without stability
    • Usually enzymatic- esterases
  • Still active/working after modifications

Question 5

Carboxylic acid-containing drugs (linked as esters)

Answer 5

• Ester are readily synthesized from carboxylic acids-containing parent drug and an alcohol-containing carrier
• Esters are easily hydrolyzed by various and ubiquitous esterases
• Large libaryof alcohols allow great variety of properties to the prodrug

Question 6

Use & applications of prodrugs

Answer 6

1. Reduction of toxicity e.g. cyclophosphamide
2. Improve water solubility e.g. chloramphenicol
3. Modify lipophilicity- sustained release
4. Improve chemical stability e.g. dinoprostone
5. Modify metabolic stability- PK e.g. esters
6. Improve taste e.g. clindamycin palmitate
7. Site-specific delivery e.g. dopamine/levodopa

Question 7

Enhanced lipophilicity- Sustained release

Answer 7

• Flupenthixol- potent neuroleptic and tranquilliser used in the treatment of schizophrenia
• Very fast onset of action, with lots of side effects
• The pro-drug increases time between doses due to depot like action- release slowly over time

Question 8

Flupenthixol decanoate formulation

Answer 8

• With oral formulation there are lots of peaks and throughs- less time in TI can also dip into sub-therapeutic and toxic levels

Question 9

Advantages of flupenthixol decanoate, a lipophilic ester

Answer 9

• Reduce the number and frequency of doses
• Reduce peak and trough effects
  
  • Reduction in toxicity
• Reduce overall dosage required
• Eliminates night-time administration
• Better patient compliance
  
  • Because of better control- behavioural
  • Clear that dose has been delivered

Question 10

Taste masking- solubility suppression

Answer 10

• Clindamycin
• Antibacterial
• Bitter tasting, taste masking will aid compliance
• Drugs to be tastes must be soluble in the mouth to interact with the taste buds, reducing solubilty while in the mouth will improve taste

Question 11

Clindamycin, antibiotic

Answer 11

• Hydroxy- groups = bitter taste
• The new formulation, injection
• Make ester pro-drug, which ester
• Palmitate, most lipophilic ester
• Paediatric formulation, USP unique selling point
• As you make the drug more lipophilic palatability increased

Question 12

Taste masking clindamycin

Answer 12

Question 13

Metabolic stability: Modification of stability of esters

Answer 13

• Ester hydrolysis in rat serum
• Esterase activity depends upon alkyl residue
• E.g. size modifying fit to the active site
• More complexity = greater half-life, increase stability means more likley the drug will reach its required site

Question 14

Stability of esters, metabolic stability

Answer 14

• Acetate half life3 min= unstable, easily hydrolysed by esterase (enzymes)
• Isopropyl ester, t-butyl ester bulkier more stable
• More stable ester, ester of benzoic acid
• Aromatic ester, also most crystalline, best mp

Question 15

Applications of prodrugs

Answer 15

• Site-specific delivery
  
  • Transport system
  • Site-specific enzyme activation

Question 16

Pro-drugs

Answer 16

• Site-specific transporter system
• Selective site delivery by using a natural amino acid transporter
• Example: Levodopa

Question 17

Site-specific delivery

Modification of transport

Answer 17

• Deficiency in Parkinson’s disease
  
  • Hydrophilic and protonated at body pH
  • Very water-soluble
• Low lipid solubility- poor GIT and BBB transport
• DA is not absorbed into the brain

Question 18

Site-specific delivery

Use of natural carrier systems

Answer 18

• L-DOPA- absorbed by an amino-acid transport system and can cross BBB
• Undergoes activation to DA via DOPA decarboxylase
• But ~20% reaches circulation- rest suffers metabolism
• Decarboxylation- systemic dopa decarboxylase
• O-methylation- Catechol-O-methyl transferase
• Conjugation and oxidation
• Usually used with a DOPA-decarboxylase inhibitor
  
  • Carbidopa
  • Benserazide

Question 19

Targeting specific transporters

Answer 19

• Levodopa is a substrate for the neutral amino transporters present at the BBB
• After brain entry, levodopa is decarboxylated to DA, which can act locally, being no longer a substrate for the neutral amino acid transporter
• To increase the systemic half-life of levodopa, it has become customary to co-administer peripherally acting inhibitors of DOPA decarboxylase

Question 20

Prodrugs Site specific enzyme activation

Answer 20

• Selective cleavage at the site to active drug
  
  • Minimal conversion elsewhere in the body.
  • Fosfestrol
    *

Question 21

Site-specific delivery

Enhanced enzyme activity in cancer cells

Answer 21

• Probably result of rapid metabolism than unique occurence
• We use a phosphate linker; this is because in cancer cells there is a very high level of expression of phosphatase enzymes so rapid degradation in the target (cancer cells) will occur (there not high in other parts of the body)

Question 22

Fosfestrol, phosphate prodrug

Answer 22

• Fosfestrol= stilboestrol diphosphate
• Synthetic oestrogen used in prostatic cancer
• Phosphate enhances water solubility
• Concept: Enhanced enzyme activity
  
  • Concept- amidase, phosphatase enhanced activity in tumour cells
• Phosphate cleaved by enzyme phosphatase
• Phosphatase activity enhanced in a target tissue
• Overall selectivity delivered to the site of action, tumour cells with higher enzyme activity

Question 23

Selective release phosphatase distribution

Answer 23

• Alkaline phosphatase is significantly raised in tumour lines

Question 24

Limitations

Answer 24

• Phosphate esters are
  
  • Polar
  • Poorly absorbed
  • Probably have to encapsulate in a carrier molecule (nanoparticle)
• Tumours are often
  
  • Poorly perfused
  • Difficult to access

Question 25

What you should be able to do

Answer 25

• Define the term ‘prodrug’
• Identify strategies, which benefit from prodrug design
• Quote examples of each application
  
  • And illustrate it with named examples
• Recognise prodrugs used in therapy
  
  • By inspection of their structure
  • And identify the advantages of prodrug design