Asian J. Research Chem. 2(2): April.

-June, 2009 ,


Prodrug as a chemical delivery system: A Review
Alka Verma1, Bhupesh Verma1, Sunil Kumar Prajapati2 and Kishu Tripathi3
1 2

Saroj Institute of Technology and Management, Lucknow (UP) India Department of Pharmacy, Bundelkhand University, Jhansi (UP) India 3 Surya College of Pharmacy, Lucknow (UP) India

The development of prodrugs promises to be very effective method for treatment of diseases in future. This approach has several advantages over conventional drug administration. Prodrugs design to maximize the amount of an active drug reaching its target through changing the physicochemical, biopharmaceutical or pharmacokinetic properties of drugs. It also includes characteristics development and classification, effect of prodrug on solubility, permeability and targeted challenge.


Key words: Prodrug, delivery system
Almost all drugs possesses some undesirable physicochemical and biological properties. Their therapeutic efficacy can be improved by minimizing or eliminating the undesirable properties while retaining the desirable one’s. This can be achieved through biological, physical or chemical means. • The biological approach is to alter the route of administration which may or may not be acceptable to patient. • The physical approach is to modify the design of dosage form such as controlled drug delivery of drug. • The third and best approach in enhancing drug selectivity while minimizing toxicity, is the chemical approach for design of prodrugs.1,2,3 What is Prodrug? The term prodrug refers to a pharmacologically inactive compound that is converted to an active drug by a metabolic biotransformation which may occur prior, during and after absorption or at specific target sites within the body.4 According to IUPAC (International Union of pure and applied chemistry): Prodrug is defined as any compound that undergoes biotransformation before exhibiting its pharmacological effects. 5


Why to use Prodrugs? a) Improve patient acceptability (decrease pain on injection) b) Alter or improve absorption. c) Alter biodistribution. d) Alter metabolism e) Alter elimination.6 Characteristics of Prodrugs In recent years numerous prodrugs have been designed and developed to overcome barriers to drug utilization such as: • Low oral absorption properties • Lack of site specificity • Chemical instability • Toxicity • Bad taste • Bad odour • Pain at application site 7,8,9 The following characteristics of prodrugs must be improved for site specific drug delivery: • The prodrug must be readily transported to site of action. • The prodrug must be selectively cleaved to active drug utilizing specific enzymes. • Once prodrug is selectively generated at site of action, the tissue must retain the active drug without further degradation.

Received on 16.12.2008 Accepted on 02.06.2009

Asian J. Research Chem. 2(2): April.-June, 2009 page 100-103

Modified on 12.05.2009 © AJRC All right reserved


This can be overcome by taking advantage of fact that -gultamyl derivatives of amino acid and peptides selectively accumulates in kidney.11 SolutionThese problems can be overcome by: • Targeting the drug to its site of action by altering its disposition characteristic. .Composed of one carrier (group) attached to the drugs. Such prodrugs have greatly modified lipophilicity due to the attached carrier and the active drug is released by hydrolytic cleavage. and perhaps. amine to aldehyde to carboxylic acid) 10.once it is excreted into urinary tract.-June. relative to its conversion at other sites. where it is supposed to be attacked. Asian J. Tripartat. Research Chem. • There are several approaches to drug targeting and prodrug design is one of them. Such a derivative of dopamine. whose design is based on site specific conditions such as lack of oxygen in cells i. which is acidic as a result of bacterial infection. to be a prodrug. Prodrugs are the ones where the active drug is covalently linked to an inert carrier transport moiety.Carrier group is attached via linker to drug. which has antibacterial properties.-glutamyl trapazamine (TPZ) is a bioreductive drug that exhibits greatly enhanced cytotoxicity in hypoxic cells. it encounters urine.Two drugs linked together. which are frequently radiation resistant and chemoresistant. 2) Once the prodrug reaches the site of its action. The example of prodrug.14. on reaching the kidney it is acted upon successively by two enzymes that are present in high concentration in renal tissue. either chemically or enzymically. while retaining the catecholamine itself as an active component. However. 2009 . Selective uptake system Dopamine.12 For site specificity: 1. Site specificity: The most important feature of efficient drug is right site of action. The site specific delivery can be obtained by tissue specific activation of the prodrug which results of metabolism by an enzyme that is either unique for tissue or present at higher concentration if we compare with other tissues. It is the biological precursor of Dopamine and may be considered.Classification of Prodrugs A) Carrier linked prodrug: • Contain a group that can be easily removed enzymatically (such as ester) to reveal the true drugs. • Ideally the group removed is pharmacologically inactive and nontoxic while the connecting bond must be labile for efficient activation in vivo. B) Bioprecursors: Metabolized into a new compound that may itself be active or further metabolized to an active metabolite (e. other bioreductive drugs into a P450/P480 reductase based gene therapy strategy for cancer treatment18. it must be selectively cleaved yielding the active drug.glutamyl transpeptidase and L-aromatic amino acid decarboxylase to release the active drug dopamine locally. It can be further subdivided intoBipartate.This is useful for treatment of urinary tract infections. An example of site specific prodrug is diethyl stilbestrol diphosphate.15. It is necessary to deliver the drug precisely to the affected part of body. produce Vasodilation of renal tissue by binding to specific receptor in kidney and this can be used to treat renal hypertension.Same principle can be used to deliver sulfonamides selectively to kidneys. TPZ exhibits particularly good activity when combined with alkylating agent such as cyclophosphamide (CPA) These findings suggests the potential benefit of incorporating TPZ. 3) Once selectively generated at site of action. the compound disintegrate spontaneously to form formaldehyde.13. • At least three following factors should be optimized to obtain a prodrug acting at specific site: 1)Prodrug must be directly transported to the site of action.16 (2) For Urinary tract infection: Hexamine is a stable inactive compound at pH greater than 5. the prodrug used are M-acyl. The increased oral bioavailability of catecholamine. the therapeutic index of dopamine is small as it precipitates high blood pressure by interaction with adrenergic receptor. This increase in dopamine levels produces a marked increase in renal blood flow. They are generally esters or amides.a neurotransmitter. However. in mere acidic pH. Stability and Resistance The drug must be resistant to degradation in different body parts and fluids. L-DOPA is the most important prodrug that is used in treatment of Parkinson’s diseases. The 101 . 2(2): April. Mutual Prodrugs. the active drug must be retained by tissue. 17 (3) Anticancer chemotherapeutic agent: These are cytotoxic because they attack growing normal cells. The normal pH of blood is slightly alkaline and so the drug circulate in the body as unchanged.e hypoxic cells. which is designed for treatment of breast cancer.. is achieved by protection of hydroxyl and amino groups.g. and uptake at the site must be rapid and essentially perfusion rate must be limited. However.

70.used for treatment of narcotic dependence and alcoholism.Primplaskan H. for e. http://www.. One of the major metabolites is the o-glucuronide. IUPAC Pure and appl. 25.1998. where carrier used in is another biologically active drug instead of some inert molecule.ingentaconnet.-June. However. prodrug development will surely decrease side/toxic effect of drugs and also trigger development of more potent primary drugs. and studies of its properties lead to the design of better drugs. esters of salicylic acid.. It accumulates in the gastric mucosal cells.25 Site specificity is central to the prodrug development strategy.. Mutual prodrug design is really do not differ from general drug discovery process in which a unique substance is observed to have desirable pharmacological effects. 22 Prodrugs can be used to afford drugs that would be too toxic to be given directly. Aspirin. in future there will be prodrugs for every known drug to make them effective in treatment drug discovery and prodrug development appear to be complementary for the generation of target specific medicines of future.K. The hemisuccinate ester was designed to block glucuronide formulation resulting in 8-fold increase in plasma levels of propanolol.. Essentials of medical pharmacology.Joseph.R.4th edition .opioid antagonist.23 Poor patient Acceptability Some drugs have a revolting taste. One way to reduce this problem is to decrease their solubility in water so that they do not dissolve on the tongue. The newest discoveries of molecular biology provide essential information about enzymes and carriers proteins. As an alternative. 2. Bahl C. .com/content/maik/biry/2002/00 0000067/00000010/0 0458028?crawler=true. Prodrugs are used to overcome several undesirable properties in order to achieve the best clinical drug application. from the first pass elimination resulting in decreased bioavalibility of oral doses compared to intravenous injections. CONCLUSION REFERENCE 1.Lee Vincent H.1129-1143 102 . 2009 . The hydroxyl groups on the catechol ring are usually protected by formation of di-o-pivaloyl or di-o-benzoyl esters. 5. pargyline is used. it is a highly irritating chemical and causes allergic reactions. which suffers. regarding all enzymes or receptors.89-116 Tripathi K. chem. 5Jan. As the unrevealing of the microbiological details of affected targets become clear.19 Prodrug may protect a drug from first pass effects. Mutual prodrug is a type of carrier linked prodrug. Even though at present prodrug are not prevalent in clinical use.20 Naltrexone (NTX) . A mutual prodrug consist of two pharmacologically active agents coupled together so that each act as a promoiety for the other agent and vice versa. The prodrugs Hetacillin lock up the offending amino group in -ring and prevents decomposition reaction by bacterial -lactamases.D. propranolol .protecting groups are designed to be less susceptible to metabolism and to gradual dissociation from the catecholamine molecule in-vivo.1998. Controlled Drug Delivery fundamental and application . -blocker and antihypertensive drug. The prodrug that is converted to the active drug at the target site itself greatly reduced side effects of highly toxic drugs.suppresses gastric irritation. Research Chem.1-2. which is quickly hydrolyzed once swallowed. 3. the drug undergoes hydrolysis on its own to release ampicillin and acetone. At present the research in this area is at a nascent stage due to lack of information. It is clear from the foregoing that design of drug cannot be based just on chemical synthesis.g the bitter taste of antibiotic Chloramphenicol can be avoided by Asian J. 2(2): April..Sileno A. most suitable for targeting purposes. The antibacterial agent ampicillin is decomposed because of the intermolecular attack of side chain amino group on the lactam ring.Demeireles J.337369. Transdermal NTX delivery is desirable to help to improve patient compliance in order to increase the delivery rate of NTX across human skin. using palmitate ester.D. There are also other prodrugs of Dopamine and of analogues of catecholamine. a feature of the slow release. poor bioavailability etc. Propanaldehyde is useful for aversion therapy in patients addicted to alcohol. Salicylic acid is a good pain-killer but causes gastric irritation and bleeding because of carboxyl group. 4. Robinson R.A therapeutically significant drug may have limited utilization in clinical practice because of poor organoleptic properties..24 Mutual Prodrug.21 Toxicity Derivative of salicylic acids are one of the oldest example that are characterized by lesser toxicity than their parent drugs.P. 2nd edition. a closely related compound. and Remeo V. Drug discovery and prodrug and soft drugs development appears to be complementary for generation of target specific medicine now and in the future.L. designed to cross the blood brain barriers (BBB) and to centrally undergo slow hydrolysis to give the active species. Once the drug has been administered.Vol 29.

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