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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.
Abstract
INTRODUCTION:
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.
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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.
Prodrugs are the ones where the active drug is covalently linked to an inert carrier transport moiety. They are generally esters or amides. Such prodrugs have greatly modified lipophilicity due to the attached carrier and the active drug is released by hydrolytic cleavage, either chemically or enzymically. It can be further subdivided intoBipartate- Composed of one carrier (group) attached to the drugs. Tripartat- Carrier group is attached via linker to drug. Mutual Prodrugs- Two drugs linked together. B) Bioprecursors: Metabolized into a new compound that may itself be active or further metabolized to an active metabolite (e.g. amine to aldehyde to carboxylic acid) 10. Site specificity: The most important feature of efficient drug is right site of action. It is necessary to deliver the drug precisely to the affected part of body, where it is supposed to be attacked. 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, and uptake at the site must be rapid and essentially perfusion rate must be limited. 2) Once the prodrug reaches the site of its action, it must be selectively cleaved yielding the active drug, relative to its conversion at other sites. 3) Once selectively generated at site of action, the active drug must be retained by tissue.11 SolutionThese problems can be overcome by: Targeting the drug to its site of action by altering its disposition characteristic. There are several approaches to drug targeting and prodrug design is one of them.12 For site specificity: 1. Selective uptake system Dopamine,a neurotransmitter, produce Vasodilation of renal tissue by binding to specific receptor in kidney and this can be used to treat renal hypertension. However, the therapeutic index of dopamine is small as it precipitates high blood pressure by interaction with adrenergic receptor. This can be overcome by taking
advantage of fact that -gultamyl derivatives of amino acid and peptides selectively accumulates in kidney. Such a derivative of dopamine, on reaching the kidney it is acted upon successively by two enzymes that are present in high concentration in renal tissue, - glutamyl transpeptidase and L-aromatic amino acid decarboxylase to release the active drug dopamine locally. This increase in dopamine levels produces a marked increase in renal blood flow.Same principle can be used to deliver sulfonamides selectively to kidneys, the prodrug used are M-acyl- -glutamyl Sulfonamides.13,14,15,16 (2) For Urinary tract infection: Hexamine is a stable inactive compound at pH greater than 5. However, in mere acidic pH, the compound disintegrate spontaneously to form formaldehyde, which has antibacterial properties.This is useful for treatment of urinary tract infections. The normal pH of blood is slightly alkaline and so the drug circulate in the body as unchanged. However,once it is excreted into urinary tract, it encounters urine, which is acidic as a result of bacterial infection. 17 (3) Anticancer chemotherapeutic agent: These are cytotoxic because they attack growing normal cells. An example of site specific prodrug is diethyl stilbestrol diphosphate, which is designed for treatment of breast cancer. 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. The example of prodrug, whose design is based on site specific conditions such as lack of oxygen in cells i.e hypoxic cells,is trapazamine (TPZ) is a bioreductive drug that exhibits greatly enhanced cytotoxicity in hypoxic cells, which are frequently radiation resistant and chemoresistant. TPZ exhibits particularly good activity when combined with alkylating agent such as cyclophosphamide (CPA)
These findings suggests the potential benefit of incorporating TPZ, and perhaps, other bioreductive drugs into a P450/P480 reductase based gene therapy strategy for cancer treatment18.. 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 Parkinsons diseases. It is the biological precursor of Dopamine and may be considered, to be a prodrug. The increased oral bioavailability of catecholamine, while retaining the catecholamine itself as an active component, is achieved by protection of hydroxyl and amino groups. The
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protecting groups are designed to be less susceptible to metabolism and to gradual dissociation from the catecholamine molecule in-vivo. There are also other prodrugs of Dopamine and of analogues of catecholamine, designed to cross the blood brain barriers (BBB) and to centrally undergo slow hydrolysis to give the active species. The hydroxyl groups on the catechol ring are usually protected by formation of di-o-pivaloyl or di-o-benzoyl esters. The antibacterial agent ampicillin is decomposed because of the intermolecular attack of side chain amino group on the lactam ring. The prodrugs Hetacillin lock up the offending amino group in -ring and prevents decomposition reaction by bacterial -lactamases. Once the drug has been administered, the drug undergoes hydrolysis on its own to release ampicillin and acetone.19 Prodrug may protect a drug from first pass effects, propranolol , -blocker and antihypertensive drug, which suffers, from the first pass elimination resulting in decreased bioavalibility of oral doses compared to intravenous injections. One of the major metabolites is the o-glucuronide. The hemisuccinate ester was designed to block glucuronide formulation resulting in 8-fold increase in plasma levels of propanolol.20 Naltrexone (NTX) ,opioid antagonist,used for treatment of narcotic dependence and alcoholism. Transdermal NTX delivery is desirable to help to improve patient compliance in order to increase the delivery rate of NTX across human skin.21 Toxicity Derivative of salicylic acids are one of the oldest example that are characterized by lesser toxicity than their parent drugs. Salicylic acid is a good pain-killer but causes gastric irritation and bleeding because of carboxyl group. It accumulates in the gastric mucosal cells. Aspirin, esters of salicylic acid,suppresses gastric irritation. 22 Prodrugs can be used to afford drugs that would be too toxic to be given directly, a feature of the slow release. Propanaldehyde is useful for aversion therapy in patients addicted to alcohol. However, it is a highly irritating chemical and causes allergic reactions. As an alternative, a closely related compound, pargyline is used. The prodrug that is converted to the active drug at the target site itself greatly reduced side effects of highly toxic drugs.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, for e.g the bitter taste of antibiotic Chloramphenicol can be avoided by
using palmitate ester, which is quickly hydrolyzed once swallowed.24 Mutual Prodrug- A therapeutically significant drug may have limited utilization in clinical practice because of poor organoleptic properties, poor bioavailability etc.
Mutual prodrug is a type of carrier linked prodrug, where carrier used in is another biologically active drug instead of some inert molecule. 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. 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, and studies of its properties lead to the design of better drugs.25 Site specificity is central to the prodrug development strategy. Even though at present prodrug are not prevalent in clinical use, 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. At present the research in this area is at a nascent stage due to lack of information, regarding all enzymes or receptors, most suitable for targeting purposes. As the unrevealing of the microbiological details of affected targets become clear, prodrug development will surely decrease side/toxic effect of drugs and also trigger development of more potent primary drugs. Prodrugs are used to overcome several undesirable properties in order to achieve the best clinical drug application. The newest discoveries of molecular biology provide essential information about enzymes and carriers proteins. It is clear from the foregoing that design of drug cannot be based just on chemical synthesis. Drug discovery and prodrug and soft drugs development appears to be complementary for generation of target specific medicine now and in the future.
CONCLUSION
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