User:DannyCyclone/PHRM

Draft = Prodrugs

Prodrugs are biologically inactive substances which are metabolished within the body (in vivo) in order to become active metabolite which exerts the desired pharmacological effects. It generally consists of a parent drug covalently bonded to an inert molecule, the promoiety. The prodrug approach has become a widely used and recognised tool for enhancing absorption, distribution, metabolism and excretion (ADME) of drugs within the human body. They provide the potential to increase aqueous solubility, enhance permeability and bioavailability, reduce toxicity and improve drug targeting.

Prodrugs can be broadly classified in two main ways chemical classes and mechanism of action. Carrier linked, bioprecursors, macromolecular and drug-antibody conjugates are examples of chemical classes whereas mechanism of action refers to type of transformation, such as enzymatic or hydrolysis. Carrier-linked prodrugs are the most common of the four types; they contain a promoiety that can be easily removed with the body. The second class, bioprecursors, are drugs that do not contain a promoiety yet still undergo chemical transformation before they become pharmacologically active. An example is codeine which is naturally converted within the body to morphine. Macromolecular prodrugs on the other hand include those in which the active substance is held via intermolecular forces within a cycli-macromolecule. Whereas drug-antibody conjugates are drugs in which the active compound is carried within cell-specific antibodies, such as those used to treat cancer.

As mentioned previously carrier-linked prodrugs are the common but only certain functionalities are adaptable when designing such drugs. That is typically only compounds with carboxylic acid, hydroxyl, amine, carbonyl or phosphates functionalities are applicable to prodrug design. These groups correlate directly to the physiochemical issues associated with the parent drug. The most commonly designed prodrugs for example contain one or more ester groups. These ester groups derive from the conversion of the parent drugs’ carboxylic acid and hydroxyl groups. The conversion into ester functionalities improves the drug’s lipophilicity and hence oral absorption by masking the effect of charged carboxylic and hydroxyl groups. After it enters the bloodstream, the prodrug is then converted back into the parent drug and the promoiety by the hydrolysis of any esters groups by esterase enzymes, predominately found in the blood and liver. While the promoiety is eliminated harmlessly from the body the active drug is now bioavailable at the desired site of action. Ampicillin and enalapril are examples of drugs converted into prodrugs to increase their oral absorption.

Previously the development of prodrugs has been used in conjunction with the more traditional forms of drug discovery, such as highthroughput screening or combinatorial chemistry. In the past these processes have produced numerous new chemical entities (NCE’s) that have been discarded due to numerous poor drug-like properties, but otherwise had high pharmacological potency. The conversion of such NCE’s into prodrugs has solved many of the physiochemical issues encountered often leading to more potent and less toxic medicines. The use of prodrug design has also been especially useful in improving the physiochemical properties of currently marketed drugs and also to create previously impossible formulations. Prodrugs have also been discovered serendipitously during clinical trials when researchers determined that what was thought to be the active drug was metabolised into a more active metabolite. Codeine is an example of one such discovery. Currently however prodrug design has been used in the early stages of drug discovery by focusing on enzyme or cell specific targets. This type of prodrug design can be used to reduce the cytotoxicity of chemotherapy treatments as it is relatively nontoxic until it reaches the cancerous cells. An example of this is being developed to treat hypoxic cancer cells that are resistant to chemotherapy and radiotherapy by using prodrugs that target reductase enzymes present in large quantities in the cells. It is postulated that in the future, every drug will be delivered in prodrug form.

As the prodrug has low cytotoxicity prior to this activation, there is a markedly lower chance of it attacking healthy non cancerous cells which reduces the side-effects associated with these chemotherapeutic agents.

Sometimes the use of a prodrug is untintentional, however, especially in the case of serendipitous drug discoveries, and the drug is only identified as a prodrug after extensive drug metabolism studies. Some prodrugs, such as Codeine and Psilocybin, also occur naturally

Prodrugs can be classified into two types based on their sites of conversion into the final active drug form.

Examples:

Enalapril is converted by esterase to the active enalaprilat

Valacyclovir is converted by esterase to the active acyclovir

Fosamprenavir is hydrolysed to the active amprenavir

Simvastatin, omeprazole, acyclovir

It is postulated that in the future, every drug will be delivered in prodrug form.

Hypoxic cells resistance to chemotherapy and radiotherapy