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Prodrugs or Drugs Latenation

Prodrugs or Drugs Latenation.

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Prodrugs or Drugs Latenation

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  1. Prodrugs or Drugs Latenation

  2. HISTORY:* In 1958. Albert defined the term prodrug as a pharmacologically inactive cpd that is transformed by the mammalian system into an active substance by either chemical or metabolic means. Harper in 1959 introduced the term“ Drug Latenation” refer to drugs that were specifically designed to require bioactivation.

  3. The type of prodrug to be produced depends on:1- the specific aspect of the drug's action that requires improvement and2- the type of functionality(function group) that is present in the active drug.Objective from prodrug to:1- improve patient acceptablity of the agent 2- reduce pain associated with administration), 3-alter absorption.4-alter distribution, 5- alter metabolism, or 6- alter elimination.

  4. Recently, the terms hard drugs and soft drugs were introduced.Hard drugs: are cpds that r- designed to contain the structural cc‾ necessary for pharmacological activity but in a form that is not susceptible to metabolic or chemical transformation. Characteristics of hard drugs:• Production of toxic metabolites is avoided•Increased efficiency of action• it may be Less readily eliminated

  5. soft drugs: are active cpds that after exerting their desired pharmacological effect r- designed to undergo metabolic inactivation to give a nontoxic product.Thus soft drugs r- considered to be the opposite of prodrugs.

  6. There r- a variety of mechanisms by which this conversion may be accomplished. 1-most often carried out by metabolizing enzymes within the body.2- by chemical means (e.g.. hydrolysisor decarboxylation). although this is less common.

  7. Prodrugs can be conveniently grouped into:1-Carrier-linked prodrugs 2-Bioprecursor prodrugs3-Mutual prodrugs

  8. CARRIER-LINKED PRODRUG PRINCIPLE Carrier-linked prodrugs r- drugs that have been attached through a metabolically labile linkage to another molecule, the so-calledpromoiety Drug Chemical synthesis + Temporary Transporter (Carrier) Regeneration in vivo Prodrug

  9. Advantages of carrier-linked prodrugs:- increased absorption.- alleviation of pain at the site of injection if the agent is given parenterally (injection site pain relief)-Elimination unpleasant taste(associated w- D)- decreased toxicity- decreased metabolic inactivation- increased chemical stability- prolonged or shortened action

  10. In addition,the Promoiety(carrier) should be: - inert not have activity but may impart some desirable property to the drug, such as increased lipid or water solubility or site-directed delivery.

  11. Ex:Chloramphenicol ,wn administration of a drug parenterally may cause pain at the site of injection, especially if the drug begins to precipitate out of solution and damage the surrounding tissue. This situation can be remedied by preparing a drug w- increased solubility in the administered solvent.

  12. The succinate ester used is inactive as an antibacterial agent, so it must be converted to chloramphenicol for this agent to be effective.

  13. The ability to prepare ester type prodrugs depends, of course, on the presence of either a hydroxyl group or a carboxyl moiety in the drug molecule.The promoiety should be easily and completely removed after it has served its function and should be nontoxic. as is indeed the case with succinate.

  14. The selection of the appropriatepromoiety depends on which properties r- sought for the agent.1- If it is desirable to increase water solubility. Then a promoiety containing an ionizable function or numerouspolar functional groups is used. 2- If on the other hand, the goal is to increase lipid solubility or decrease water solubility, a nonpolar promoiety is appropriate.

  15. A slight variation on the carrier-linked prodrug approach is seen with mutual prodrugs in which the carrier also has activity. The antineoplastic agentEstramustine, which is used in the ttt of prostatic cancer,Estramustine is composed of a phosphorylated steroid ( 17α-estradiol) linked to a normustard [HN(CH2CH2CI)2] through acarbamate linkage.The steroid portion of the molecule helps to concentrate the drug in the prostate, where hydrolysis occurs to give the normustard and CO2

  16. The normustard then acts as an alkylating agent and exerts a cytotoxic effect.The17α-estradiol has an antiandrogenic effect on the prostate and therapy, slows the growth of the cancer cells. Since both the steroid and the mustard possess activity. estramustine is termed a mutual pradrug.

  17. Note:the phosphorylation of the estradiol can be used to increase the water solubility, which also constitutes a prodrug modification. Both types of esters(carbamates and phosphates) r- hydrolyzed by chemical or enzymatic means.

  18. Bioprecursor prodrugs:In contrast to carrier-linked prodrugs. bioprecursor prodrugs contain no promoiety but rather rely on metabolism introduce the functionality necessary to create an active For example, the nonsteroidal anti-inflammatory drug (NSAID) sulindac is inactive as the sulfoxide and must reduced metabolically to the active sulfide

  19. Sulindac is administered orally, absorbed in the small intestine, and subsequently reduced to the active species.Administration of the inactive form has the benefit of reducing the gastrointestinal (GI) irritation associated with the sulfide.

  20. This example also illustrates one of the problems associated with this approach, namely, participation of alternate metabolic paths that may inactivate the compound. In this case, after absorption of sulindac, irreversible metabolic oxidation of the sulfoxide to the sulfone can also occur to give an inactive cpd.

  21. Although seen less frequently, some prodrugs rely on chemical mechanisms for conversion of the prodrug to its active form. For example. hetacillin is a prodrug form of ampicillin in which the amide nitrogen and α-amino functionalities have been allowed to react with acetone to give an imidazolidinone ring system .This decreases the basicity of the α-amino group and reduces protonation in the small intestine so that the agent is more lipophilic.In this manner,

  22. In such an approach. the added moiety, or promoiety, in this case acetone, must be nontoxic and easily removed after it has performed its function.

  23. Prodrugs of functional groups. there are a variety of different types of prodrugs. The major types of prodrugs (grouped according to functional group) and bioprecursor drugs (grouped according to type of metabolicactivation)

  24. 1-Carboxylic Acids and Alcohols:Prodrugs of agents that contain carboxylic acid or alcohol functionalities can often be prepared by conversion to an ester.

  25. This is the most common type of prodrug because of the ease with which the ester can be hydrolyzed to give the active drug. Hydrolysis is normally accomplished by esterase enzymes present in plasma and other tissues that are capable of hydrolyzing a wide variety of ester linkage.

  26. a number of the different types of esterases that prodrugs may use: *Ester hydrolase*Lipase*Cholesterol esterase*Acetylcholinesterase*Carboxypeptidase*Cholinesterase

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