Rabu, 03 Februari 2010






Historically, the term prodrug or proagent was coined by Albert in the late 1950s to denote chemical derivatives that could temporarily alter the physicochemical properties of drugs in order to increase their therapeutic utility and reduce associated toxicity.

Prodrugs also have been synonymously referred to as latentiated drugs, bioreversible derivatives, and congeners.

However, the term prodrug gained wider acceptance and usually describes compounds that undergo chemical transformation within the body prior to exhibiting pharmacologic activity.

Ø Some of the earliest examples of prodrugs are methenamine and aspirin.
In the early stages, prodrugs were obtained fortuitously rather than intentionally; an example is prontosil, which was discovered in the 1930s and later identified as a prodrug of the antibiotic sulfanilamide.

                       Phenytoin (a) and fosphenytoin (b)



Þ Definition:

Prodrug is a drug that is prepared by chemically modifying a pharmacologically active species to form a new entity that undergoes transformation to the active species within the body.

Þ The modification alters the physicochemical and biopharmaceutical properties of the drug in some beneficial manner.

Þ An ideal prodrug should:

1.  Possess no pharmacological activity

2.  Be eliminated more slowly than its rate of cleavage to the parent

3.  Be nontoxic

4.  Be inexpensive to prepare


             Typical path of enzymatic hydrolysis of esters and amides

     Þ Prodrugs can be used to:

1.  increase or decrease the aqueous solubility

2.  mask bitterness

3.  increase or decrease lipophilicity

4.  improve absorption
5.  decrease local side effects, and

6.  Alter tissue distribution of the parent molecule.




1.  without altering the primary contour of the parent drug, changes its physicochemical and biopharmaceutical properties for the better

2.  protects vulnerable groups and stabilizes the molecule

3.  generally either esters or amides of parent drugs

4.  improve their lipophilicity and they can easily cross the lipophilic barriers and enter the systemic circulation

5.  guides the drug to a target site (site specificity)

6.  improve solubility, stability, and bioavailability

7.  masks unpleasant tastes and odors

8.  restricts drug toxicity.

               Þ Some examples of prodrugs:

1.  a. Chloramphenicol has an aqueous solubility of 2.5 mg/mL

Chloramphenicol sodium succinate, a prodrug, has an aqueous solubility of 100 mg/mL

b. Hydantoins also possess low aqueous solubilities that result in low and variable availability and precipitation following injection.

The ethyl and triethylamine esters of diphenylhydantoic acid, prodrugs which have improved aqueous solubilities by adding an amine function to the molecule.

Chloramphenicol palmitate is used extensively in pediatric preparations due to its better organoleptic acceptance

2.  The perception of taste requires that some minimum aqueous concentration be exceeded so that the taste can be detected; so that the bitterness can be masked by reducing solubility.

Chloramphenicol palmitate:
                            is less soluble than its base form.
                            is used extensively in pediatric preparations
                               due to its better organoleptic acceptance

Clindamycin 2-palmitate has no bitterness of the parent antibiotic.

Clindamycin 2-phosphate caused little pain and irritation when given by i.m. compared to its parent drugs.

Procaine-penicillin G
Benzathine-penicillin G

                                        Show resistance to aqueous hydrolysis in
                                                   comparison to their parent drugs

Testosterone cypionate:
        The prodrug of testosterone
        Long acting than the parent drug when given in an oil base

Fluphenazine enanthate and naloxane pamoate:
   Showed longer duration of actions vis-à-vis their parent drugs

Acetaminophen ethyl vinyl ether has an aqueous solubility lower than the acetaminophen but the bioavailability after oral administration in dogs is similar.

Þ Membrane permeability is governed in part by the lipophilicity of a compound.

Þ Highly polar compounds have low lipophilicity and therefore low membrane permeability.

Epinephrine is a compound of this type and very effective in the treatment of glaucoma, but it produces a myriad of side effects such as hyperemia, mydriasis, corneal edema, and allergic sensitivity.

A prodrug, the dipivaloyl ester of epinephrine was found to be devoid of cardiac symptoms (with no effect on heart rate or blood pressure) and effective in lowering intraocular pressure.

Þ Oral administration of aspirin can result in gastrointestinal bleeding.
     The bleeding has been attributed to local irritation due to the acidic
     of the carboxylic acid substituent.

The GI irritation could be reduced by blocking of both the charge and the acidic nature of the aspirin such as in the prodrug of aspirin (acylal-aspirin).

Þ Altering the tissue distribution of a compound to transport the drug molecule to the site of action is an important delivery method.

This method can produce striking results when the site of action is the brain and the blood-brain barrier must be crossed.

A prodrug of 2-PAM (N-methylpyridinium-2-aldoxime), i.e., dihydropyridine:

          1. 2-PAM is a cholin esterase-reactivating compound
2.  Is lacking the polar quaternary ammonium entity  
3.  Was able to cross GI mucosa and the blood-brain barrier (BBB).
4.  In the brain, oxidation produces 2-PAM, and permitting cholinesterase reactivation.

Þ  Pivampicillin (a prodrug of ampicillin):
            ©   A quite lipophilic compound
            ©   Produces high blood levels of ampicillin

Þ  Proteins and small peptides:
          ©    New and important classes of drugs

©  yet they do not pass readily through biomembrane

©  easily metabolized by peptidases

©  the prodrugs show:
a.  enhanced delivery 
b. enhanced chemical stability
c.   break down rapidly in the body to release the biologically active parent compound

The prodrugs which have been made:

a.  thyrotropin-releasing hormone (TRH)

b. luteinizing hormone-releasing hormone (LH-RH)

c.   fibrinopeptides

d. collagen

Þ  Mitomycin C:
©  a useful antibiotic against neoplastic disease

©  it does not differentiate in its action against tumor and normal cells

©  prodrug of mitomycin-dextran has been made and its activity against various tumors is greater than the un-complexed mitomycin 

Þ  Mercaptopurine:
©  together with methotrexate is used in the chemotherapy of lymphocytic leukemia
©  when taken orally is only about 50% absorbed
©  Acyloxymethyl mercaptopurine, a prodrug, has a better absorption through hairless skin.

Ø                  Ocular and Dermal Drug Delivery

§ Many drugs applied on cornea or skin fail to show their best due to the resistance offered by the corneal or epidermal layers.

§ Dipivalate ester of epinephrine showed 100 fold increased in its

§ Dermal delivery prodrugs may be convenient alternatives for
     systemic action.

This could be done by making the drug non-polar.

The successful delivery of prodrug through the skin requires the following sequential steps :

1.  dissolution and diffusion of drug molecules in the vehicle into the skin surface,
2.  partitioning of the drug into the stratum corneum (SC),  
3.  diffusion of the drug into the SC, and
4.  partitioning of the drug into the epidermis and dermis and uptake into the blood circulation.

Based on these requirements, the desired parameters for transdermal prodrugs include:
1.  low molecular mass (preferably less than 600 Da),
2.  adequate solubility in oil and water to maximize the membrane concentration gradient (the driving force for diffusion),
3.  optimal partition coefficient, and
4.  low melting point.

Ø                     Site and Cell Specificity

§ Drug may be made site specific by preparing their prodrugs.

§ Catecholamines have been made to cross blood barrier, which is otherwise impermeable to parent drugs

§ Prodrugs linked with antibodies, hybridoma cells and liposomes may become cell specific, not just site specific.

                                                The End

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