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    Drug Affecting Metabolism by Rinku

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    Rinku Kundu
    This document summarizes the key phases and processes of drug metabolism in the human body. It discusses that drugs undergo biotransformation through two main phases: Phase I involves functionalization reactions like oxidation, reduction, and hydrolysis that make the drug more polar. Phase II involves conjugation reactions where functional groups are added to make drugs more hydrophilic and able to be excreted, such as conjugation to glucuronic acid, sulfate, glycine, or glutathione. Cytochrome P450 enzymes, particularly family 1, 2, and 3, are responsible for many Phase I oxidation reactions in the liver. Factors like genetics and environment can impact an individual's drug biotransformation.

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    Drug Affecting Metabolism by Rinku

    Uploaded by

    Rinku Kundu
    47 views23 pages
    This document summarizes the key phases and processes of drug metabolism in the human body. It discusses that drugs undergo biotransformation through two main phases: Phase I involves functionalization reactions like oxidation, reduction, and hydrolysis that make the drug more polar. Phase II involves conjugation reactions where functional groups are added to make drugs more hydrophilic and able to be excreted, such as conjugation to glucuronic acid, sulfate, glycine, or glutathione. Cytochrome P450 enzymes, particularly family 1, 2, and 3, are responsible for many Phase I oxidation reactions in the liver. Factors like genetics and environment can impact an individual's drug biotransformation.

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    It's all about drug which affects on metabolism

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    drug affecting metabolism by Rinku

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    This document summarizes the key phases and processes of drug metabolism in the human body. It discusses that drugs undergo biotransformation through two main phases: Phase I involves functionalization reactions like oxidation, reduction, and hydrolysis that make the drug more polar. Phase II involves conjugation reactions where functional groups are added to make drugs more hydrophilic and able to be excreted, such as conjugation to glucuronic acid, sulfate, glycine, or glutathione. Cytochrome P450 enzymes, particularly family 1, 2, and 3, are responsible for many Phase I oxidation reactions in the liver. Factors like genetics and environment can impact an individual's drug biotransformation.

    Copyright:

    © All Rights Reserved
    Download as PPTX, PDF, TXT or read online from Scribd
    Download as pptx, pdf, or txt
    47 views23 pages

    Drug Affecting Metabolism by Rinku

    Uploaded by

    Rinku Kundu
    This document summarizes the key phases and processes of drug metabolism in the human body. It discusses that drugs undergo biotransformation through two main phases: Phase I involves functionalization reactions like oxidation, reduction, and hydrolysis that make the drug more polar. Phase II involves conjugation reactions where functional groups are added to make drugs more hydrophilic and able to be excreted, such as conjugation to glucuronic acid, sulfate, glycine, or glutathione. Cytochrome P450 enzymes, particularly family 1, 2, and 3, are responsible for many Phase I oxidation reactions in the liver. Factors like genetics and environment can impact an individual's drug biotransformation.

    Copyright:

    © All Rights Reserved
    Download as PPTX, PDF, TXT or read online from Scribd
    Download as pptx, pdf, or txt
    of 23

    Drug Metabolism

    Presenter : -
    Rinku Kundu (B.pharm)

    Dr Swaroop HS copyighted 1
    Outline
    • Introduction
    • Phases of Metabolism
    • Phase I Metabolism
    • Cytochrome P family
    • Phase II Metabolism
    • Factors affecting Biotransformation

    Dr Swaroop HS copyighted 2
    Introduction
    • Biotransformation: Chemical alteration of
    the drug in body that converts nonpolar
    or lipid soluble compounds to polar or
    lipid insoluble compounds
    • Consequences of biotransformation
    • Active drug  Inactive metabolite :
    Pentobarbitone, Morphine, Chloramphenicol
    • Active drug  Active metabolite: Phenacetin
    • Inactive drug  active metabolite: Levodopa

    Dr Swaroop HS copyighted 3
    Phases of Metabolism
    • Phase I
    • Functionalization reactions
    • Converts the parent drug to a more polar
    metabolite by introducing or unmasking a
    functional group (-OH, -NH2, -SH).
    • Phase II
    • Conjugation reactions
    • Subsequent reaction in which a covalent
    linkage is formed between a functional
    group
    on the parent compound or Phase I
    metabolite and an endogenous substrate
    such
    as glucuronic acid, sulfate, acetate, or an
    amino acid
    Dr Swaroop HS copyighted 4
    Phases of Metabolism
    Hydrolytic Reactions
     Esters, amides, epoxides Oxidation
    and  Aromatic moieties, Olefins
    arene oxides by epoxide hydrase  Benzylic & allylic C atoms
    and a-C of C=O and C=N
    Phase II -  At aliphatic and alicyclic C
    Phase I -  C-Heteroatom system
    Conjugation
    Functionalization  C-N (N-dealkylation, N-
    oxide formation, N-
    hydroxylation)
     C-O (O-dealkylation)
    Drug  S-dealkylation
    Metabolism  S-oxidation, desulfuration
     Oxidation of alcohols and
    aldehydes,
     Conjugation Miscellaneous
     Glucuronic acid Reduction
     Sulfate, Glycine and other AA  Aldehydes and ketones
     Glutathione or mercapturic acid  Nitro and azo
     Acetylation, Methylation  Miscellaneous

    Dr Swaroop HS copyighted 5
    Phase I / Non Synthetic Reactions
    Oxidation
    • Addition of oxygen/ negatively charged radical
    or removal of hydrogen/ positvely charged
    radical.
    • Reactions are carried out by group of mono-
    oxygenases in the liver.

    Dr Swaroop HS copyighted 6
    Cytochrome P450 enzymes
    • Monooxygenase enzyme family
    • Major catalyst: Drug and endogenous
    compound oxidations in liver, kidney, G.I. tract,
    skin and lungs.
    • Location: smooth endoplasmic reticulum.
    • The reductase serves as the electron source for
    the oxidative reaction cycle

    Dr Swaroop HS copyighted 7
    Cytochrome P
    family
    • Multiple CYP gene families have been identified in
    humans, and the categoriezed based on protein
    sequence homology
    • Most of the drug metabolizing enzymes are in CYP
    1, 2, & 3 families .
    • Frequently, two or more enzymes can catalyze the
    same type of oxidation, indicating redundant and
    broad substrate specificity.

    Dr Swaroop HS copyighted 8
    Reduction
    • Converse of oxidation
    • Addition of Hydrogen / positively charged radical
    or removal of Oxygen / negatively charged
    radical
    • Drugs primarily reduced are chloralhydrate,
    chloramphenicol, halothane.

    Dr Swaroop HS copyighted 9
    MICROSOMAL REDUCTION

    A.NITRO Reduction- RNo2 RNH2


     Chloramphenicol to aryl amine metabolite

    O OH
    B.KETO Reduction - R-C-R1 R-CH-R1
     Cortisone to Hydrocortisone,
    C. AZO Reduction
    Prontosil to Sulfanilamide

    NON MICROSOMAL REDUCTION

     Chloral hydrate to Trichloro ethanol


    c) HYDROLYSIS

     Drug is split combining with water


     Ester + water Esterases Alcohol & Acid
     Microsomal hydrolysis Pethidine to
    meperidinic acid

     Non microsomal hydrolysis –


    Esterases,Amidases & Peptidases
    Atropine to Tropic acid
    Cyclization and Decyclization

    • Cyclization
    • Formation of ring structure from a straight
    chain compound
    • E.g. Proguanil

    • Decyclization
    • Opening up of ring structure of the cyclic
    drug molecule
    • E.g. Barbiturates, Phenytoin.

    Dr Swaroop HS copyighted 13
    PHASE II REACTIONS
    CONJUGATION
    / TRANSFER
     Drug / phase I metabolite combines with
    endogenous substance derived from
    carbohydrates/ proteins.
     covalent bond formation between
    functional group
    of drug & endogenous substrate
     Endogenous-Glucuronic acid,Amino acids,
    Sulfates,Acetates,Glutathione
     Represent terminal inactivation – True
    detoxification
    reactions.

    Conjugates-

    hydrophilic

     ionized,
     ↑mol.weight,
     inactive

     Excreted in urine/ bile/ faeces.


     Phase II- need energy
     6 types of reactions
    1.CONJUGATION WITH
    GLUCURONIC ACID
     UDP glucuronyl transferases
     Conjugates with OH & COOH are conjugated with
    glucuronic acid derived from glucose

    Drug + UDPGA Microsomal Glucuronyl


    transferase

    Drug glucuronide + UDP


     Drugs - Aspirin,Paracetamol,PABA,
    Metronidazole,Morphine,
    Diazepam
     ↑Mol.weight – favours biliary excretion

     Drug glucuronides excreted in bile are hydrolyzed


    by intestinal microfloral enzymes - parent drug
    released - reabsorbed into systemic circulation-
    ↓excretion ↑duration of action
    - Oral contraceptives, Phenolphthalein

     Endogenous substrates -
    Steroid,Thyroxine,Bilirubin
    2. ACETYLATION
     Drugs with Amino or Hydrazine
    groups - INH,PAS,Hydralazine,Sulfonamides
    Procainamide,Dapsone.

     R-NH2 N Acetyl R-NHCOCH3


    transferase
    Acetyl CoA
     Genetic polymorphism
     Acetylation- Rapid / Slow
    3. CONJUGATION WITH
    SULFATE
     Drug groups-Amino, Hydroxyl

     Cytoplasmic Enzymes - Sulfotransferases /


    Sulfokinases.

     Methyl dopa, Steroids,


    Chloramphenicol, Warfarin
    4. CONJUGATION WITH
    GLYCINE
     Drug group – Carboxylic acid
     Salicylic acid , Benzoic acid

    5. CONJUGATION WITH GLUTATHIONE

     Drug groups-Epoxide, Quinone


     Toxic metabolites of Paracetamol, Ethacrynic acid
     Cytoplasmic Enzyme - Glutathione S- Transferase
    6. METHYLATION

     Drugs with Amino & Phenol groups

     Histamine, Adrenaline, Nicotinic acid,


    Dopamine, Methyl dopa, Captopril

     Enzyme- Methyl transferase


    RIBONUCLEOTIDE /RIBONUCLEOSIDE
    SYNTHESIS

     Action of Purine & Pyrimidine antimetabolites


     6 Mercaptopurine
    Thank You
    Dr Swaroop HS copyighted 23

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