Tam Nguyen November 25, 2014 CHEM4201

 Introduction  What is prodrug?  Why use prodrugs?  Classification of prodrugs  Applications of prodrugs  Esters  Enalapril  Conclusion  References

 Metabolism is an essential pharmacokinetic process, which renders lipid soluble and non- polar compounds to water soluble and polar compounds so that they are excreted by various processes.  Drugs are considered xenobiotics and most are extensively metabolized in humans.  Not all drugs are bioavailable, in which this led to the development of prodrugs.

 Prodrug is a pharmacological substance administered in an inactive form.  Once administered, the prodrug is metabolized in vivo into an active drug within the body through metabolic process, such as hydrolysis of an ester form of the drug.

 Improve membrane permeability  Improve absorption and distribution  Improve solubility  Alter metabolism  Alter toxicity  Alter elimination

 Carrier-linked prodrugs:  Simple prodrug that contains an active drug linked with a carrier group that is removed enzymatically.  The carrier group must be non-toxic and biologically inactive when detached from drug.  Bioprecursors:  A compound that is metabolized by molecular modification into a new compound that may itself be active or further metabolized to an active metabolite.

 Pharmaceutical applications  Improvement of taste  Improvement of odour  Reduction of irritation  Reduction of pain on injection  Enhancement of drug solubility and dissolution rate  Enhancement of chemical stability of drug  Pharmacokinetic applications  Enhancement of provability  Prevention of pre-systemic metabolism  Prolongation of duration of action  Reduction of toxicity  Site specific drug-delivery

 Esters are the most commonly employed prodrugs.  Numerous catalytic esterases are present in vivo to hydrolyze simple esters. Prodrug Active Form of Drug

 The monoethyl ester of enalaprilat  Enalaprilate was first discovered as an inhibitor of angiotensin converting enzyme (ACE) and used to treat hypertension.  Due to its high polarity, note two COOH’s, it was not orally bioavailable, and thus needed to be administered by injection.

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 Prodrugs are inactive compounds which are converted to active drugs in the body by the process of drug metabolism.  Prodrugs were design to improve pharmacokinetic and drug delivery properties.  Esters are commonly used as prodrugs to make a drug less polar and allowing it to cross cell membranes more easily.  The nature of the ester can be altered to vary the rate of hydrolysis.

 Brochure  concept and application of prodrugs

 Alagarsamy, V. (2010). Textbook of medicinal chemistry (Vol. 1, pp ). New Delhi: Reed/Elsevier.  Testa, B., & Mayer, J. (2003). Hydrolysis in drug and prodrug metabolism: Chemistry, biochemistry, and enzymology. Zu ̈ rich: VHCA.  Drug Metabolism. (n.d.). Retrieved November 18, 2014, from tics_of_drugs/drug_metabolism.html  Rautio, J., Kumpulainen, H., Heimbach, T., Oliyai, R., Oh, D., Järvinen, T., & Savolainen, J. (n.d.). Prodrugs: Design and clinical applications. Nature Reviews Drug Discovery, Retrieved November 18, 2014, from  Pharmacological Effects, Prodrugs (Definition, Examples) and Sources of Drug Information. (n.d.). Retrieved November 18, 2014, from Prodrugs-Definition-Examples-and-Sources-of-Drug-Information