Lesson 3 Jezko Biotransformation of Drugs

download Lesson 3 Jezko Biotransformation of Drugs

of 48

  • date post

    04-Jun-2018
  • Category

    Documents

  • view

    222
  • download

    0

Embed Size (px)

Transcript of Lesson 3 Jezko Biotransformation of Drugs

  • 8/13/2019 Lesson 3 Jezko Biotransformation of Drugs

    1/48

    Biotransformation of drugs

    PharmDr. Pavol Jeko

    Center of Excellence PharmacyDepartment of Medicinal Chemistry

    CADD Laboratory

    Faculty of Pharmacy, Comenius University

    Odbojarov 10, 832 32 Bratislava, Slovakia

    Tel: + 421 250 117 221

    e-mail: jezko@fpharm.uniba.sk;p.jezko@gmail.com

  • 8/13/2019 Lesson 3 Jezko Biotransformation of Drugs

    2/48

    Drug metabolizms it is a biochemical modification or degradation of

    drugs

    drugs are partly eliminated unchanged or partiallyi r n f rm m li h n r

    excreted as metabolites

    drug metabolism is also of great importance in

    medicinal chemistry because it influences (inqualitative, quantitative, and kinetic terms) thedeactivation, activation, detoxification, andtoxification of the vast majority of drugs

    2

  • 8/13/2019 Lesson 3 Jezko Biotransformation of Drugs

    3/48

    OBJECTIVEOBJECTIVE::

    conversion of lipophilic

    compounds that are easier

    eliminated

  • 8/13/2019 Lesson 3 Jezko Biotransformation of Drugs

    4/48

    XENOBIOTIXENOBIOTICSCS

    substances that do not naturally occur in the body

    (that enter the body ), are not necessary for thephysiological development and have no

    drugs (health)

    agrochemicals (agriculture) pesticides, herbicides, fertilizers

    food additives

    flavoring agents, coloring agents, preservatives, stabilizers

    4

  • 8/13/2019 Lesson 3 Jezko Biotransformation of Drugs

    5/48

    Places of drug biotransformation liver: the majority of metabolic reactions

    kidney: 2 phase guts: 2 phase

    blood (ester hydrolysis)

    lasma h drol sis of esters

    within a cell:

    endoplasmic reticulum (microsomes)

    enzymes cytochrome P450 (CYP-450)

    mitochondria

    cell cytosol

  • 8/13/2019 Lesson 3 Jezko Biotransformation of Drugs

    6/48

    CONSEQUENCES

    ofBIOTRANSFORMATION

    bioinactivation:

    usually products are less active or inactive

    bioactivation:

    in some cases, the metabolic process converts

    non-active substance on its own active form(prodrug)

    6

  • 8/13/2019 Lesson 3 Jezko Biotransformation of Drugs

    7/48

    TYPES OF BIOTRANSFORMATION

    REACTIONS

    drug metabolism takes place in two steps:

    first phase - functionalization reactions the molecule introduces a new functional group, usually polar (-COOH,-OH,-NH2)

    the polar group can serve as a reaction point for the second reaction phase

    second phase - conjugation reactions includes the addition of endogenous molecules (glucuronic, sulphate) to the

    metabolite of 1 phase

    (prerequisite for conjugation reactions is the presence of a suitable chemical group(-COOH,-OH,-NH2)

    results of both phases are metabolites more soluble in water ,

    and thus easier elimininated

  • 8/13/2019 Lesson 3 Jezko Biotransformation of Drugs

    8/48

    Type of reaction The reaction pathway

    Oxidation aromatic or aliphatic hydroxylationN- or S-oxidation

    N-, O- or S-dealkylation

    Reactions of 1 phase drug metabolism

    Reduction Reduction NO2 group to hydroxylamine andamine

    Reduction of the carbonyl to alcohol

    Hydrolysis Ester on acid and alcoholAmid on acid and amine

    Hydrazide on acid and substituted hydrazine

  • 8/13/2019 Lesson 3 Jezko Biotransformation of Drugs

    9/48

    Type of reaction Endogenous reagent or

    substrate

    Xenobiotic substrate

    Glucuronidation Uridine-diphosphate of

    glucuronic acid (UDPGT)

    Carboxylic acid, alcohol,

    phenol, amine

    Sulfation 3-phosphoadenosine-5-

    Alcohol, phenol, amine

    Reaction of 2 phase drug metabolism

    phosphosulfate (PAPS)Acetylation Acetyl-CoA Amine

    Glutathione

    conjugation

    glutathione Epoxides, compounds

    with chlorine atom

    Metylation S-adenozylmethionine Phenols, amines, thiols

    Aminoacid Glycine,glutamine Carboxylic acid

  • 8/13/2019 Lesson 3 Jezko Biotransformation of Drugs

    10/48

    1. OXIDATION1. OXIDATION incorporation of polar groups in the molecules of the drug or substitution

    of one polar group by another for increase of the polarization

    according to the character of reaction, metabolic oxidation is dividedinto several types:A. Oxidation of alkyl-compounds

    B. Oxidation of alcohols aldeh des acids

    C. Oxidative hydroxylations of aromatic compoundsD. Oxidative N and O dealkylation

    E. Oxidation to Noxids

    F. Oxidative deamination

    G. Oxidation of sulfids to sulfoxids and sulfonesH. Oxidative desulfuration

    I. Oxidative dehalogenation

    J. Oxidative opening of the ring

    10

  • 8/13/2019 Lesson 3 Jezko Biotransformation of Drugs

    11/48

    1. a) Oxidation of alkyl1. a) Oxidation of alkyl--compoundscompounds it is the most common type of oxidation on the side-alkyl chain (if

    a compound has aliphatic, aromatic or heterocyclic character)

    drugs containing aliphatic unbranched alkyls are

    easily oxidized; oxidizing of alkyls decreases with ramifications of the

    alkyl chain

    oxidation usually begins on the last carbon through

    the primary alcoholic group and proceed finally to acid

    can take place on the penultimate carbon (beta-

    oxidation), which are metabolised type of fatty acid compounds in the

    body11

  • 8/13/2019 Lesson 3 Jezko Biotransformation of Drugs

    12/48

    oxidation of pentobarbital: metabolites with prim.

    aliphatic hydroxyl or carboxyl group at the terminal methyl group

    are produced; or the sec. alcoholic group on the penultimate carbon

    atom of the alkyl is metabolised

    NH

    CH3

    O

    NH

    CH3

    O

    NH CH

    3

    3

    O

    NH CH

    3

    3

    O OH

    NH

    NH

    O

    CH3

    C

    H2

    CH3O

    O

    OH

    NH

    NH

    O

    CH3

    CH3O

    O

    OH

    O

  • 8/13/2019 Lesson 3 Jezko Biotransformation of Drugs

    13/48

    1.1. b )b ) Oxidation alkohols, aldehydes, acidsOxidation alkohols, aldehydes, acids

    aliphatic primary alkoholsaliphatic primary alkohols

    light oxidation of alcohols (prim. drug) to aldehydes (COH, sec. metab.)

    and to the acid (-COOH, final metab.)

    ahk oxidcia cez aldehydy (COH) a na kyseliny (COOH)

    tertiary alcohols are not so much metabolized

    mainly are creating glucuronide conjugates

    13

    alcohols

  • 8/13/2019 Lesson 3 Jezko Biotransformation of Drugs

    14/48

    1.1. c)c) OxidatOxidativeive hydroxylhydroxylationation ofof aromaticaromatic

    compoundscompounds ((ringsrings))

    phenolic substances are produced, the final metabolite is eliminated as

    a conjugate with glucuronic acid or sulfuric acid, which is well soluble in water

    14

    phenolic substances are produced

  • 8/13/2019 Lesson 3 Jezko Biotransformation of Drugs

    15/48

    1.1. d)d) OxidativeOxidative NN andand OO dealkylationdealkylation

    common reaction on ethers and alkylamino-drugs

    etheric bond is quite strong, so simple aliphatic ethersare often excreted unchanged, the complex ethers are metabolised partially only

    phenolic ethers are cleaved to the phenolic part and aldehyde.

    15

    alcohols

    alcohols

  • 8/13/2019 Lesson 3 Jezko Biotransformation of Drugs

    16/48

    drugs containing a tertiary or secondary amine (NH2) are

    partially metabolized to secondary and primary amines, andaldehyde

    it is assumed that N-metyl-derivates are dealkylatedthrough the N-oxides and N-hydroxymetyl-derivates by the

    scheme:

    16

  • 8/13/2019 Lesson 3 Jezko Biotransformation of Drugs

    17/48

    1.1. e)e) OxidationOxidation toto NNoxids (Noxids (Noxidation)oxidation)

    drugs with tertiary amino-group

    17

    alcohols

  • 8/13/2019 Lesson 3 Jezko Biotransformation of Drugs

    18/48

    1. f) Oxidative deamination drugs, which contains the primary aliphatic amines are metabolised by monoamineoxidase (MAO). These reactions vary according to the nature of the amine.

    phenylethylamine-type drugs are oxidized to aldehyde and acid and ammonia:

    substances like aryl-isopropylamine are oxidized to ketone

    18alcohols

  • 8/13/2019 Lesson 3 Jezko Biotransformation of Drugs

    19/48

    1.1. g)g) OxidationOxidation ofof sulfides to sulfoxidssulfides to sulfoxids

    andand sulfonessulfones

    thioethers type drugs - this type of biotransformation is

    common in the group of phenothiazines

    19

    alcohols

  • 8/13/2019 Lesson 3 Jezko Biotransformation of Drugs

    20/48

    1.1. h)h) Oxidative desulfurizationOxidative desulfurization

    some sulphur-compounds are oxidized by oxidative desulfurization,

    the sulfur atom will be refund for oxygen atom in drug molecule (S O)

    (some thiobarbiturates are oxidized to barbiturates)

    20

    alcohols

  • 8/13/2019 Lesson 3 Jezko Biotransformation of Drugs

    21/48

    1. i) Oxidative dehalogenation

    halogenated compounds are converted to acid

    halothane is partially metabolised by the scheme

    DDT

    21

    alcohols

    alcohols

  • 8/13/2019 Lesson 3 Jezko Biotransformation of Drugs

    22/48

    1. j) Oxidative opening of the ring

    complete destruction of the drug molecule

    22

  • 8/13/2019 Lesson 3 Jezko Biotransformation of Drugs

    23/48

    1.k) Oxidation of double bonds

    alco