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Lecture 14 Prodrug, biotransformatiion, enzyme induction and inhibition

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Lecture 14 Prodrug, biotransformatiion, enzyme induction and inhibition

  1. 1. Session VI Pro-drug, Biotransformation of drugs, enzyme induction, enzyme inhibition and Entero-hepatic circulation. Aphasia DR. GHULAM SAQULAIN M.B.B.S., D.L.O., F.C.P.S HEAD OF DEPARTMENT OF ENT CAPITAL HOSPITAL, ISLAMABAD
  2. 2. PRODRUG  Prodrug is an inactive substance/drug that is converted to a drug within the body by the action of enzymes or other chemicals.  About 5-7% of drugs approved worldwide can be classified as prodrugs
  3. 3.  Rationale for Prodrug Design A. Improving Formulation and Administration B. Enhancing Permeability and Absorption C. Changing the Distribution Profile D. Protecting from Rapid Metabolism and Excretion E. Overcoming Toxicity Problems F. Managing the Life Cycle
  4. 4.  The prodrug approach is a strategy to increase the utility of pharmacologically active compounds, because one can optimize any of the properties as well as prolong the commercial life cycle of potential drug  Phosphate esters are a widely used prodrug strategy for improving the aqueous solubility. The active parent drug molecule is rapidly released from phosphate prodrugs by endogenous phosphatases, such as alkaline phosphatase.
  5. 5.  Prednisolone sodium phosphate is a classic example of a phosphate prodrug It is a highly water-soluble  Also masks the unpalatable taste of prednisolone tablets.
  6. 6. BIO TRANSFORMATION (Drug Metabolism) Definition  Chemical reactions which lead to modification of drugs. Importance of metabolism  Termination of drug action  Enhance excretion by transforming the drug to a less lipid soluble, less readily reabsorbed form.
  7. 7. Organ sites of drug metabolism  Liver (the major site).  Intestinal Mucosa and Lumen  Kidney  Skin  Lung  Plasma
  8. 8. TYPES OF METABOLIC REACTIONS  Phase I Reactions  Phase II Reactions
  9. 9. Phase I reactions  Oxidation.  Reduction.  Hydrolysis. Phase II reactions  Conjugation reactions
  10. 10. Oxidation Reactions Microsomal oxidation (CYT-P450(. Oxidation by cytochrome P450 enzymes Non-microsomal oxidation. Oxidation by soluble enzymes in cytosol or mitochondria of cells (as oxidases and dehydrogenases( e.g. monoamine oxidase (MAO( and alcohol dehydrogenase.
  11. 11. Reduction reactions  Microsomal reduction  Non microsomal reduction Hydrolysis  All are non microsomal  Drugs affected are either esters or amides  Hydrolysis occurs by enzymes (esterases or amidases) e.g. acetylcholine and lidocaine
  12. 12. Phase I reactions can result in  Inactivation of drug (termination of action)  Conversion of active drug to another active metabolite.  Conversion of drugs to toxic metabolites. Paracetamol → acetaminophen hepatotoxicity  Activation of pro-drug  Product might undergo phase II.
  13. 13. Conjugation of metabolite (phase I) with endogenous substance as methyl group, acetyl group, sulphate, amino acid or glucouronic acid to produce conjugate that is water soluble and easily excreted. Phase II Conjugation Reactions
  14. 14. Types of conjugation reactions Conjugation reaction Enzyme required glucouronide conjugation glucouronyl transferase Acetylation N-acetyl transferase Sulphation Sulfotransferase Methylation methyl transferase Amino acids conjugation
  15. 15. Phase II reactions:  All are non microsomal except glucouronidation  Deficieny of glucouronyl transferase enzyme in neonates may result into toxicity with chloramphenicol (Gray baby syndrome).
  16. 16. Characteristics of Phase II Products  Usually make drug Pharmacologically inactive.  Polar  more water soluble.  more readily excreted in urine.
  17. 17. Factors affecting metabolism  Age  Nutrition  Genetic Variation  Diseases  Gender  Degree of Protein Binding  Enzyme Induction & inhibition  Route of Drug Administration
  18. 18. ENZYME INDUCTION  Enzyme induction is a process in which a molecule (e.g. a drug) induces (i.e. initiates or enhances) the expression of an enzyme.
  19. 19. ENZYME INHIBITION  Enzyme inhibition can refer to the inhibition of the expression of the enzyme by another molecule  Interference at the enzyme-level, basically with how the enzyme works. This can be competitive inhibition, uncompetitive inhibition, non- competitive inhibition or partially competitive inhibition.
  20. 20. Enzyme inhibition and inhibition of metabolism Leads to drug accumulation and toxicity

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