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Biotransformation

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Biotransformation Prepared by Prof .Abdulkader.H.El Daibani * Biotransformation Biotransformation (metabolism) of drugs: As most drugs are lipid soluble ... – PowerPoint PPT presentation

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Title: Biotransformation


1
Biotransformation
  • Prepared by
  • Prof .Abdulkader.H.El Daibani

2
Biotransformation
  • Biotransformation (metabolism) of drugs
  • As most drugs are lipid soluble and be
    reabsorbed, biotransformation is essential for
    termination of action and elimination of drugs.

3
Biotransformation
  • Drug metabolism lead to
  • 1) Increase polarity of drugs by converting lipid
    soluble drugs into water soluble drugs and
    therefore enhance excretion.
  • 2) Inactivation of drugs
  • a) most drugs form inactive metabolites.
  • b) With some drugs both the parent drug and the
    metabolite are active.
  • e.g.
  • Diazepam ? oxazepam
  • Herion ? Morphine

4
Biotransformation
  • c) Other drugs, the parent drug is inactive
    (prodrug) and the metabolite is active and formed
    by hydrolysis of an ester or amide bond e.g.
  • enalapril ? enalaprilate
  • L-dopa ? dopamine
  • Talampicillin ? ampicillin
  • Cyclophosphamide ? 4-ketocyclophosphamide

5
Biotransformation
  • Loss of activity or formation of active
    metabolites occurs mainly in phase I reaction
    where a functional group is introduced or
    exposed. if not rapidly excreted in urine, the
    metabolites of phase I undergo conjugation in
    phase II reactions to form highly polar
    conjugates which are generally inactive and
    rapidly excreted renally.

6
Biotransformation
  • Sites of drug metabolism
  • The liver is the major organ of drug metabolism,
    although other sites (lungs, kidneys, plasma,
    small intestine. Placenta, skin and brain) may
    contribute.
  • Cytochrome P450 monooxygenase or mixed function
    oxidase (M.F.O) system is the major catalyst of
    drug biotransformation reaction and located in
    smooth endoplasmic reticulum (SER) of liver and
    other tissues.

7
Biotransformation
  • Enzymes presented in S.E.R are called Microsomal
    enzyme.
  • Non-microsomal enzymes are located in
    mitochondria cytosole phase I enzyme are located
    in S.E.R. while phase II enzyme are located in
    the cytosol.
  • Most drugs are metabolized by phase I (oxidation)
    followed by phase II (conjugation) with
    glucouronic acid in some cell.
  • e.g.
  • PI PII
  • paracetamol ? P-OH ?
    P-OH-Gu
  • ( p) Oxi Conj.

8
Biotransformation
  • In human 12 cytochrome P450 gene families have
    been identified.
  • The cyto.P450 1, P4502, P4503,(CYP1, CYP2,CYP3).
  • Encode the enzyme involved in the majority of
    drug transformation.
  • CYP3A4,CYP2D6 are involved in the metabolism of
    all drugs. as a result of low substrate
    specificity among cyt.P450 proteins, two or more
    enzymes may catalyze a given metabolic reaction.

9
Biotransformation
  • Biochemical pathways of drug biotransformation
  • 1)phase I (Non synthetic) reactions
  • loss of activity or formation of active
    metabolites occur in phase I ,enzyme of phase I
    located in S.E.R.
  • a) Oxidation
  • Most important phase I reactions and involve
    (M.O.F) system.
  • Aliphatic oxidation tolbutamide,Ibuprofen.
  • Aromatic oxidation propranolol, phenytoin
  • S oxidation cimetidine, chloropromazine(CPZ)
  • N-Oxidation paracetamol,dapsone.
  • N-dealkylation morphine,imipramine.
  • O-dealkylation codeine,indomethacin.
  • Oxidation deamination diazepam,amphetamine.

10
Biotransformation
  • Cytochrome P450 independent oxidation
  • Amine oxidases (M.AO) sympathomimetic
    (adrenaline, Noradrenaline)
  • Dehydrogenase-ethanol.
  • Oxidative stress
  • is a harmful consequence of drug oxidation
    leading to toxicity or carcinogenicity due to
    formation of highly reactive intermediates(FR)
    (free radicals) capable of damaging specific
    cellular components, also some diseases e.g.
    parkinsonism may be due to oxidative stress.

11
Biotransformation
  • b)Reduction
  • Microsomal and non microsomal.
  • Nitroreduction Chloramphenicol, clorazepate .
  • c) hydrolysis
  • ester-succinylcholine, aspirin, procaine by non
    specific estrase in liver and other tissue.
  • Amide Lidocaine, Indomethacin by specific
    estrase in liver.
  • Peptide-insulin, vasopressin by protease and
    peptidases in plasma, erythrocyte and other
    tissue.

12
Biotransformation
  • II) phase II (conjugation) reactions
  • Also called synthetic reaction because drug or
    metabolite binds with polar endogenous substance
    to form water soluble conjugate which is readily
    eliminated by kidney or in bilegt300 in M.W.
  • The drug must possess a chemically active group
    (mainly-OH introduced-phase I) to which the
    conjugation substance is attached.
  • The most imp. conjugation reactions are
  • a) Glucuronidation.
  • b) Sulphation.
  • c) Acetylation.
  • d) Methylation.
  • e) Conjugation with glutathione.
  • f) Conjugation with amino acids.

13
Biotransformation
  • a) Glucuronidation
  • Most common phase II reaction. Catalyzed by
    glucuronyl transferase in S.E.R. in liver, kidney
    and other tissues in presence of uridie
    diphosphate glucuronate (DP-G) as glucuronate
    donor to form glucaronides which are
  • 1) Generally inactive
  • But morphine glucuronide is more active than
    morphine as analgesic.
  • 2) rapidly excreted by kidney and bile by an
    anion transport mechanism.
  • 3) May be hydrolyzed by ß-glucuronidase of
    intestinal bacterial flora to produce the parent
    drug which is reabsorbed from S.I (E.H
    circulation).

14
Biotransformation
  • Examples
  • Bilirubin, morphine, stilbesterol and
    chlormphenicol is C.I. in neonates because it may
    cause grey baby syndrome due to deficiency of
    glucuronyl transferase in neonates.
  • Most biotransformation reaction are oxidation
    followed by glucuronidation.
  • oxi. Glu.
  • Paracetamol ? para-OH ? para-O-Glu
  • phaseI phase II

15
Biotransformation
  • b) Sulphation
  • In presence of 3-phosphadenosin,
    5-phosphosulphate, steroids, heparin and a methyl
    dopa.
  • c) Acetylation catalyzed by N-acetyl transferase
    in presence of acetyl CoA as an acetyl group
    donnar limited to drug with primary-NH2.
  • e.g. Isonaizid , sulphonamides, hydralazine.
  • People who are genetically deficient in N-acetyl
    transferase are called slow acetylators and they
    may exhibit adverse effects from these drugs e.
  • INH ? Peripheral neuropathy
  • slow acetylator
  • Hyralazine and procainamide ?S.L.E
  • slow acetylator
    ( Systemic lupus erythrmatosus)

16
Biotransformation
  • d) Methylation
  • Addition of methyl group via methionine in
    presence of COMT e.g. metabolism of adrenaline
    and histamine.
  • e) Conjugation with glutathione
  • Binds with unstable potentially toxic
    intermediate metabolites e.g. epoxide,
    paracetamol metabolite to form non harmful
    compounds.
  • f) Conjugation with amino acids (Glycine and
    glutamine)
  • e.g. conjugation of aromatic carboxylic acids
    such as salicylic acid, benzoic acid and
    nicotinic acid with glycine .

17
Biotransformation
  • Factors affecting biotransformation
  • 1) Enzyme induction and enzyme inhibition.
  • 2) Genetic polymorphism (oxidation,conjugation)gen
    etic differences in the metabolism of drugs e.g.
    Isoniazid (INH) slow acetylation and fast
    acetylation.
  • 3) Environmental pollutants smoking,
    insecticides e.g D.D.T. (enzyme induction).
  • 4) Pathological factors liver disease, heart
    failure and shock (? hepatic blood flow).
  • 5) Age drug metabolism is reduced in extremes of
    age.

18
Biotransformation
  • 1)enzyme induction and enzyme inhibitionsome
    drugs stimulate (induction ) or inhibit
    microsomal enzymes in liver.
  • a) Enzyme induction causes increased
    activity of microsomal enzyme.
  • Involves de novo (synthesis of new protein).

19
Biotransformation
  • Characteristics of enzyme induction
  • 1) reversible process.
  • 2) Takes one week to appear and 2-3 weeks to
    disappear after stopping drug.
  • 3) ? weight and size of liver due to hypertrophy
    of hepatocytes.
  • Some drugs increase metabolism of other drugs and
    their own metabolism (Autoinduction) e.g.
    Carbamazepine.
  • Inducing agents are specific for a given P450
    family e.g. polycyclic aromatic hydrocarbons,
    cigeratte smoking and barbequed meat ??CYP1A
    family.
  • Glucocorticoids and anticonvulsants ??CYP3A4
    family .
  • Acetone and chronic alcohol ?? CYP2E1 family.
  • Many inducers of cyt. P450 induce enzyme involved
    in phase II reaction e.g. Glucuronyl transferase
    and glutathione transferase .

20
Biotransformation
  • Characteristics of inducing agent
  • 1) lipid soluble.
  • 2) Is a substrate for the enzyme it induces.
  • 3) Has long t 1/2.
  • 1) Clinically importance of enzyme inductions may
    occur e.g. failure of oral contraceptive or loss
    of anticoagulant, effect of warfarin following
    Rifampin.
  • 2) Pharmacokinetic tolerance due to antiinduction
    with antiepileptic drug e.g. carbamazepine and
    others.

21
Biotransformation
  • 3) useful in therapy- phenobarbitone induces
    bilirubin conjugation so used in treatment of
    Hyperbilirubinemia.
  • 4) Disease may result ( Itarogenic Effect)
    antiepilptics ? metabolism and elimination of
    vit.D ? leads to vit. D deficiency? osteomalasia
    in adults or rickits in children.

22
Biotransformation
  • B) Enzyme Inhibition
  • Reduction in enzyme activity after exposure to
    some drugs e.g. cimetidine and ketoconazol
    inhibit oxidation of drugs by forming tight
    complex with heam-iron of cyp P450.
  • Erythromycin inhibit CYP3A and its metabolites to
    form a complex with heam of iron of CYP 450.
  • Other enzyme inhibitors include INH, sodium
    valproate, metronidazole and ciprofloxacin.
  • Enzyme inhibition tend to be more selective than
    enzyme induction.

23
Biotransformation
  • Enzyme inhibitor ?metabolism of
    clinical effect
  • Cimetidine warfarin
    bleeding
  • Chloramphenicol tolbutamide
    hypoglycemia
  • Erythromycin terfenadineor astrmizole
    arrthmias
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