A) Carrier linked prodrugs and B) Bioprecursors A) Carrier linked prodrugs- active drug linked to a carrier group Carrier group- should be labile, non-toxic, biologically inactive Further divided to bipartate, tripartate and mutual prodrugs 1. Bipartate- prodrug with carrier 2. Tripartate- carrier + linker + prodrug 3. Mutual prodrug- synergistic drugs connected to each other

1. Prodrugs
• Initially used by Albert
• Is a pharmacologically inactive compound that is converted
into an active drug by a metabolic biotransformation

2. • Can be enzymatic/non-enzymatic
• Non-enzymatic such as hydrolysis- compounds may cause
stability problems
• Conversion can occur before ADME or at specific site in the body
• Soft drug- pharmacologically active and uses metabolism for
promotion of excretion

3. Why prodrug
Lead modification approach used to correct a flaw in drug candidate
•Aqueous solubility
•Absorption and distribution
•Site specificity
•Instability
•Prolonged release
•Toxicity
•Poor patient acceptability
•Formulation problems

4. Types of Prodrugs
• A) Carrier linked prodrugs and B) Bioprecursors
A) Carrier linked prodrugs- active drug linked to a carrier group
• Carrier group- should be labile, non-toxic, biologically inactive
Further divided to bipartate, tripartate and mutual prodrugs
1. Bipartate- prodrug with carrier
2. Tripartate- carrier + linker + prodrug
3. Mutual prodrug- synergistic drugs connected to each other

5. Increase
solubility
Lipophilic isopropyl ester
hydrolysed by corneal
esterases

6. Ampicillin + CH2 (linker) + Pivalic acid carrier = Pivampicillin increase lipophilicity high bioavailability

7. Ampiciliin + Sulbactum (β lactamase inhibitor) = sultabactum (increase pharmacokinetics)

8. Sulfoxide
converted to
thioether
GIT irritation
Sulindac (Pro drug)
converted to
thioether by lever
enzyme
Low GIT irritation

9. Types of prodrugs
• B) Bioprecursors- compound metabolized by molecular
modification into new compound which can be drug
• No resemblance to desired functional group
• Drastic structural change is required to unmask desired group
• Oxidation is common metabolic biotransformation

10. Carrier linked prodrugs
• An ideal drug carrier must
• (1) protect the drug until it is at the site of action;
• (2) localize the drug at the site of action;
• (3) allow for release of the drug chemically or enzymatically;
• (4) minimize host toxicity;
• (5) biodegradable, biochemically inert, and non-immunogenic;
• (6) easy prepare inexpensively
• (7) Chemically and biochemically stable in its dosage form

11. • Most common (biologically labile) functional groups utilized in
prodrug design are shown above.

12. • Esters are the most commonly employed prodrugs.
• Numerous catalytic esterases are present in vivo to hydrolyze
simple esters.
Prodrug Active Form of Drug

13. • However, different species have differing amounts and types of
esterases with different substrate specificities and different rates
of hydrolysis.
• This can make it difficult for pharmaceutical companies to
generate accurate preclinical models in which to evaluate their
candidate prodrug.

14. • One example is the monoethyl ester of enalaprilat, which is called enalapril.
• Enalaprilate (upper left) was first discovered as an inhibitor of angiotensin converting enzyme
(ACE) and used to treat hypertension.
• Due to its high polarity, note two COOH’s, it was not orally bioavailable, and thus needed to be
administered by injection.
• The monomethyl ester, enalapril (upper right) is orally bioavailable.

15. • Another example is the anti-viral agent Oseltamavir (Tamiflu®)
shown above
• Notice that the oral bioavailability is improved by employing
the ethyl ester of the carboxylic acid

16. Prodrugs
• To minimize toxicity To Encourage Patient Acceptance
• To eliminate formulation problems Improved absorption

17. Prodrugs
• Increased water solubility
•

18. Bioprecursors
• Prontosil to sulfonamides

19. Bioprecursors
• Activation of leflunomide to active drug

20. Bioprecursors
• Sulfation activation Decarboxylation activation