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Session VI
Pro-drug, Biotransformation of drugs, enzyme induction, enzyme inhibition
and Entero-hepatic circulation.
Aphasia
DR. GHULAM SAQULAINM.B.B.S., D.L.O., F.C.P.SHEAD OF DEPARTMENT OF ENTCAPITAL HOSPITAL, ISLAMABAD
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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
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Rationale for Prodrug DesignA. Improving Formulation and AdministrationB. Enhancing Permeability and AbsorptionC. Changing the Distribution ProfileD. Protecting from Rapid Metabolism and ExcretionE. Overcoming Toxicity ProblemsF. Managing the Life Cycle
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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.
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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.
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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.
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Organ sites of drug metabolism
Liver (the major site). Intestinal Mucosa and Lumen Kidney Skin Lung Plasma
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TYPES OF METABOLIC REACTIONS
Phase I Reactions
Phase II Reactions
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Phase I reactions Oxidation. Reduction. Hydrolysis.
Phase II reactions Conjugation reactions
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Oxidation ReactionsMicrosomal 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 .
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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
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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.
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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
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Types of conjugation reactions
Conjugation reaction Enzyme required
glucouronide conjugation glucouronyl transferase
Acetylation N-acetyl transferase
Sulphation Sulfotransferase
Methylation methyl transferase
Amino acids conjugation
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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).
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Characteristics of Phase II Products
Usually make drug Pharmacologically inactive.
Polar more water soluble. more readily excreted in urine.
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Factors affecting metabolism Age Nutrition Genetic Variation Diseases Gender Degree of Protein Binding Enzyme Induction & inhibition Route of Drug Administration
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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.
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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.
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Enzyme inhibition and inhibition of metabolismLeads to drug accumulation and toxicity