Abstract
The prodrug design is an efficient and powerful method that can be practised in a wide range of parent drug compounds, administration routes and preparations. Its main goal is to overcome the drawbacks of regular drug compounds by effectively targeting the drug's particular site of action for improved therapy. This assignment seeks mainly to depict the different classifications of prodrugs and the role these play in drug design through the use of several examples. A brief description highlighting the modern aspects of prodrug design is also covered here.
Introduction:
Prodrugs are inactive forms of drug compounds that undergo chemical or enzymatic conversion inside the body to form an active drug compound. The purpose of a prodrug design is to improve the distribution of that particular drug in systemic circulation by either increasing or decreasing its aqueous and lipid solubility. Prodrugs have also been reported to improve chemical stability and reduce toxicity (Patrick, 2013). Studies have found that 10% of the drugs marketed around the world currently fall under the prodrugs category. In 2008 alone, 33% of all the totally authorized minute-molecular-weight drugs were prodrugs. (Huttunen et al; 2011)
Role of prodrugs in drug design:
Imroving and reducing water solubility
Aqueous solubility can be increased by attaching the polar neutral groups like amino acids, sugar molecules or phosphates to the parent drug (Zawilska et al; 2013). This approach is usually employed in parentral prepration in order to avoid pain at the site of injection.
Given that Prednisolone on its own is less soluble in water, attaching the phosphate molecule to the free hydroxyl group of prednisolone renders it more water-soluble and hence increases the drug's effectiveness.
Drugs that have unpleasant tastes can prove difficult to swallow as they dissolve on the tongue. This problem can be addressed by decreasing the water solubility of the drug.
Chloramphenicol, for example, tastes bitter when consumed orally. Therefore, the drug is combined with palmatic acid to form chloramphenicol palmitate, which is less soluble in water than chloramphenicol. As the palmitate ester does not dissolve on the tongue, it makes the patient more accepting of the medication (Silverman, 2012).
Improving lipid solubility
Drugs that have poor lipid solubility have been reported to lead to poor membrane permeability. This condition can be improved by converting more water soluble molecules - such as phosphate, hyroxyl, thiol, carboxyl or amine - from the parent group to more lipid-soluble groups - like alkyl or aryl ester - which can cross the fatty cell membrane with greater ease. This prodrug approach is most commonly used for oral, topical, transdermal and occular administration. Oseltamivir prodrug, which is used for the treatment of Influenza A and B virus, undergoes hydrolysis to form the active form of oseltamivir carboxylate. Converting the hydroxyl group to ester creates oseltamivir lipophilic, which can cross the cell membrane with far greater ease (Huttunen et al; 2011).
Enhancing drug stability
When administered orally, most drugs are metabolized, which serves to reduce the actual amount of the drug that reaches the target. The development of prodrug design seeks to solve this problem by attaching the carrier group to the metabolically-liable group of the parent drug thereby preventing the breakdown of drug until it reaches its intended target.
Bambuterol, for example, is a prodrug of terbutaline. It is used in asthma treatment. Terbutaline contains two metabolically liable phenol groups that lower the bioavailability of the drug. This is improved by converting the phenolic groups to N,N-dimethyl carbamate ester to obtain bambuterol, which is far more stable to hydrolysis (Huttunen et al; 2011).
Reducing toxic and side effects
In order to best attain the therapeutic benefits of an active drug , its toxicity and side effects should always be kept to a minimum level.
Doxorubicin, an anti-cancer drug, has been proven to cause cardiotoxicity. To overcome this particular side effect, a galactoside prodrug was attached to doxorubucin through the use of a carbamate spacer, which simultaneously increases the doxorubicin availability in tumor tissue and decreases its accumulation in the cardiac tissue. Moreover, the hydrophilic nature of galactoside allows it to avoid further distribution to other tissues, rendering it less toxic and more effective (Stella et al; 2007).
Increasing the duration of action
Drugs with lower half-lives require repeated dosing in order to retain blood concentration, which can leas to poor patient acceptability over time. This is solved by increasing the duration of action.
Fluphenazine deconate, which is the prodrug of fluphenazine, has long been used as a long acting IM injection to treat Schizophrenia. This injection, given once every two weeks, has been shown to increase both its effectiveness and patient acceptability (Patrick, 2013).
Regular functional groups used in prodrug design
Modern aspects of prodrug design:
In the past, the approach to prodrug design focused on altering the different physiochemical conditions such as solubility, absorption , permeability, distribution etc. However, these approaches lacked site specificity. The modern prodrug approach, by contrast, is based on molecular and cellular factors (Dahan et al; 2014). Here, the carrier molecule attach covalently to the molecule to selectively target enzymes or transporters . This innovative approach provides a far more significant prospective for enhancing drug bioavailability and choosiness amongst poorly absorbed drug molecules.
Targeting transpoters
Targeting enzymes
Enzymes are employed to increase both overall oral drug absorption and site-specific drug delivery. The use of a nutrient molecule can help provide more specific targeting in order to enhance oral absorption. In site-specific drug delivery, the active drug is released only at its intended site of action, thereby reducing the toxic effect that might be caused due to non-specific uptake by other tissues. This approach is usually used for cancer chemotherapy, in which a non-toxic drug is converted into a cytotoxic by an enzyme at the tumour site (ADEPT) or in neoplastic cells (GDEPT) (Dahan et al;
2014).
Conclusion:
Progress in molecular biology has led to equally significant changes to the pharmaceutical sciences domain. In earlier times, the prodrug methodology was only considered as a last resort option, only to be used when experts had attempted all other possible options first. Nowadays, the prodrug approach is applied at the very early stages of the development process and is now considered a more powerful and successful alternative.
Works Cited
Patrick, G. L. (2013) An introduction to Medicinal Chemistry, 5thedn. Oxford: Oxford University Press.
Thomas, G. (2003) Fundamentals of medicinal chemistry, West Sussex: John Wiley & Sons Ltd.
Silverman, Richard, B. (2012) The organic chemistry of drug design and drug action, Elsevier Science.
Dahan, A., Zimmermann, M. &Ben-Shabat, S. (2014) ‘Modern prodrug design for targeted oral drug delivery’, Molecules19, 1420-3049: 16489-16505.
Zawilska, J., Wojcieszak, J. &Olejniczak, B. (2013) ‘Prodrugs: A challenge for the drug development’, Pharmacological Reports 65, 1734-1140: 1-14.
Huttunen, M., Raunio, H. &Rautio, J. (2011) ‘Prodrugs- from Serendipity to Rational Design’, Pharmacological reviews 63, 3: 750-771.
Stella, V., Borchardt, R., Hageman, M.,Oliyai, R.,Maag, H., Tilley, J. (2007) Prodrugs: Challenges and Rewards,Springer Science & Business Media
