Lecture 10


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Lecture 10

  1. 1. Medicinal Chemistry
  2. 2. <ul><li>Drug Metabolism </li></ul>
  3. 3. <ul><li>Phase II Metabolic Routes </li></ul>
  4. 4. <ul><li>Known as conjugation reactions </li></ul><ul><li>Involve the attachment of a group or a molecule to the drug or metabolite </li></ul><ul><li>May occur at any point in the metabolism process </li></ul><ul><li>Often the final step in the metabolic pathway before excretion </li></ul><ul><li>Products of these reactions are known as conjugates </li></ul><ul><li>Normally water soluble and usually excreted in the urine and/or bile </li></ul><ul><li>Conjugates are usually pharmacologically inactive </li></ul><ul><li>Reactions commonly involved in phase II conjugation are acylation, sulphate formation, and conjugation with amino acids, glucuronic acid, glutathione, and mercapturic acid. </li></ul><ul><li>Methylation is a minor metabolic route, but it can be a major route for phenolic hydroxy groups </li></ul><ul><li>In all cases, the reaction is usually catalyzed by specific esterase </li></ul>
  5. 9. Prodrugs <ul><li>Inactive compounds that yield an active compound in the body </li></ul><ul><li>Conversion is frequently carried out by enzyme-controlled metabolic reactions and less frequently by chemical reactions within the body </li></ul><ul><li>Prodrugs are used as a way to: </li></ul><ul><li>Increase lipid or water solubility </li></ul><ul><li>Improve that taste of a drug to make it more patient compatible </li></ul><ul><li>Alleviate pain when the drug is administered parenterally by injection </li></ul><ul><li>Reduce toxicity </li></ul><ul><li>Increase chemical stability </li></ul><ul><li>Increase biological stability </li></ul><ul><li>Change the length of the time of duration of action </li></ul><ul><li>Deliver the drug to a specific site in the body </li></ul>
  6. 10. Continue… <ul><li>Prodrugs can be broadly classified into two groups: </li></ul><ul><li>Bioprecursors </li></ul><ul><li>Carriers </li></ul><ul><li>They may also be sub-classified according to the nature of their action (e.g. photoactivated drugs) </li></ul>
  7. 11. Bioprecursor Prodrugs <ul><li>Inactive compounds that are converted into the active drug form through the action of metabolism </li></ul><ul><li>Conversion may involve a single step or a series of steps </li></ul><ul><li>Oxidation, reduction, and phosphorylation are all involved in the conversion of some prodrugs into active drugs </li></ul><ul><li>Reduction reactions are not as common as oxidation </li></ul><ul><li>Phospohorylation occurs in the activation of a number of antiviral drugs </li></ul>
  8. 13. Carrier Prodrugs <ul><li>Are formed by combining an active drug with a carrier species to form a compound with the desired chemical and biological characteristics </li></ul><ul><li>The link between the drug and the carrier must be a group (e.g. ester or amide) that can be easily metabolized once absorption has occurred or the drug has been delivered to the required body compartment </li></ul><ul><li>Carrier prodrugs that consist of a drug linked by a functional group to the carrier are known as bipartate prodrugs. Tripartate drugs are those in which the carrier is linked to the drug by a link consisting of a separate structure </li></ul>
  9. 15. Continue… <ul><li>The choice of the functional group used as a metabolic link depends both on the functional groups occurring in the drug molecule and the need for the prodrug to be metabolized in the appropriate body compartment </li></ul>
  10. 16. Using prodrugs to improve absorption and transport through membranes
  11. 17. Improving Patient Acceptance <ul><li>Palmitic acid and other long chain fatty acids are often used as carriers, since they usually form prodrugs with bland taste </li></ul>
  12. 18. Slow Release <ul><li>Provided by the slow hydrolysis of amide and ester linked fatty acid carriers </li></ul>
  13. 19. Site Specifity
  14. 20. Minimizing Side Effects
  15. 21. <ul><li>THE END OF THE COURSE </li></ul>