Seminar Presentation

on

Prodrug Concept

The Prodrug Concept

The prodrug concept was first proposed by Albert in 1958.

Albert and his co-workers described prodrugs as pharmacologically inactive chemical derivatives that could be used to alter the physicochemical properties of drugs, in a temporary manner, to increase their usefulness and/or to decrease associated toxicity.

They have also been called ‘latentiated drugs’, ‘bioreversible derivatives’, and ‘congeners’.

Ideally, the prodrug is converted to the original drug as soon as the derivative reaches the site of action, followed by rapid elimination of the released derivatizing group without causing side effects in the process.

Applications Of Prodrug

Prodrugs are converted into the active drug within the body through enzymatic or non-enzymatic reactions. The various applications of prodrug approach are;

1. Improved physicochemical properties (e.g., better solubility in the intended formulation)

2. Enhanced delivery characteristics and/or therapeutic value of the drug

3. To improve drug penetration through biological membranes

4. To increase site specificity of the drug

5. To improve the drug’s stability and solubility

6. To increase duration of pharmacological activity

7. To decrease the drug’s toxicity and adverse effects

8. To improve patient acceptance.

Ideal Requirements of Prodrugs

1. The prodrug is inactive or less active than the parent compound

2. The linkage between the drug and the carrier must be cleaved in vivo

3. The carrier molecule released in vivo must be non-toxic

4. The metabolic fragments of carrier molecule, apart from the drug should be non-toxic

Classification of Prodrugs

1. Carboxylic acids and alcohols.

Prodrugs of carboxylic acid and alcohol functionalities can be prepared by conversion to an ester.

The ester can be easily hydrolysed by esterase enzymes present in plasma and other tissues to give active drug.

Enzymes: ester hydrolase, lipase, cholesterol esterase, acetylcholinesterase, carboxypeptidase

Carboxylic acids and alcohols (continued)...

Ex: Pivampicillin, talampicillin and bacampicillin are prodrugs of ampicillin.

The absorption of these prodrugs is nearly complete (98-99%) whereas that of ampicillin is < 50%.

Enalapril, the most widely prescribed ACE inhibitor, is the ethyl ester prodrug of the active diacid, enalaprilat.

Enalaprilat is poorly absorbed from the gastrointestinal tract (< 10%), but absorption of the prodrug enalapril is greatly improved (60%).

2. Amines.

Due to high chemical stability of amide linkage and lack of amidase enzymes, amines are not derivatised to amide prodrugs.

A more common approach has been to utilize mannich bases as a prodrug form of the amines.

3. Azo Linkage

Amines are derivatised to azolinkage prodrugs.

Ex: Prontosil

4. Carbonyl compounds

Carbonyl compounds such as aldehydes and ketones are converted to prodrugs.

These have generally involved derivatives in which the sp2 hybridized carbonyl carbon is converted to an sp3 hybridised carbon attached to two heteroatoms such as oxygen, nitrogen, or sulfur.

Ex: Methenamine releases HCHO in the urine, which acts as an antibacterial agent.

Developments of Prodrugs

1. To improve patient acceptance:

Clindamycin has bitter taste. It was found that by increasing the chain-length of 2-acylesters of clindamycin, the taste improved from bitter to non-bitter taste (phosphate ester).

2. To reduce gastric irritation:

Several drugs (NSAIDS, nicotinic acid, kanamycin, diethylstilboestrol) cause irritation and damage to gastric mucosa.

These problems of drugs can be overcome by changing to prodrugs.

Ex. : Salicylic acid to aspirin, nicotinic acid to nicotinic acid hydrazide

Developments of Prodrugs (continued)…

3. To improve chemical stability:

Several drugs may decompose during their shelf life or in the GIT when used orally.

The prodrug approach of such drugs is a good technique to improve stability.

Ex. : Azacytidine in aqueous solution is readily hydrolyzed but its bisulphite prodrug is stable.

4. Prodrugs for increased water solubility:

Prednisolone and methylprednisolone are poorly water-soluble corticosteroid drugs.

Prednisolone phosphate is a water-soluble prodrug of prednisolone that is activated in vivo by phosphatases.

Developments of Prodrugs (continued)…

5. To decrease drug’s toxicity and adverse effects:

Dipivaloylepinephrine prodrug instead of epinephrine to treat glaucoma.

Esterification of aspirin greatly suppresses gastric uterogenic activity.

6. To improve membrane transport:

Barbiturates are weakly acidic in nature and are converted to the corresponding sodium salt. The sodium salt is extensively employed for intravenous anaesthetic properties.

Dopamine used for the treatment of Parkinson’s disease can be improved by administering its prodrug Levo-DOPA.

Developments of Prodrugs (continued)…

7. Prolonged Activity:

Nordazepam, an anxiolytic loses activity too quickly due to metabolism and excretion.

A prodrug introduced to improve the retention characteristics is (diazepum).

8. Tissue specific prodrug design:

The site-specific drug delivery can be achieved by the tissue activation, which is the result of an enzyme unique to the tissue or present in higher concentration.

Dexamethasone is absorbed efficiently in intestinal tract and as such do not reach colon area for treatment.

when prodrugs dexamethasone-21-β-glucoside were used they were absorbed in colon more efficiently compared to their parent drugs.