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Dr. RAGHU PRASADA M S
MBBS,MD
ASSOCIATE PROFESSOR
DEPT. OF PHARMACOLOGY
SSIMS & RC.
1
It is chemical alteration of drug in the body, wherein
Non polar lipid soluble compounds are made
polar lipid insoluble, so that they are easily
excreted.
Drugs which do not undergo biotransformation –
Streptomycin, neostigmine….(highly polar
drugs)
Primary site – Liver
Others – Kidney, Intestine, Lungs, Plasma
Drug Biotransformation –convert lipophilic /
hydrophobic drug (to enter cells) to hydrophilic
metabolites.
Advantages
Termination of drug action - (↓ toxicity)
Reduced lipophilicity.
Renal / biliary excretion ↑ - (↓renal reabs)
Metabolic changes by Enzymes
( Microsomal, Cytoplasmic, Mitochondrial)
Spontaneous Molecular rearrangement –
HOFMANN ELIMINATION
Excreted unchanged (highly polar drugs) -
Aminoglycosides, Methotrexate, Neostigmine
A) Drug inactivation - inactive or less active
Propranolol, Pentobarbitone, Morphine,
Chloramphenicol, Paracetamol, Ibuprofen,
lignocaine
B) Active drug to Active metabolite- active
metabolite
Effect is due to parent drug and its active
metabolite
Phenacetin - Paracetamol
Phenyl butazone - Oxyphenbutazone
Primidone - Phenobarbitone
Diazepam - Oxazepam
Digitoxin - Digoxin
Amitriptyline - Nortriptyline
Codeine - Morphine
Spironolactone - Canrenone
Allopurinol - Alloxanthine
Cefotaxime - Des acetyl cefotaxime
Morphine - Morphine 6 glucuronide
C) Inactive drug (Prodrug) - Active drug
Prodrugs are inactive drugs which need BT in the
body to form active metabolites.
ADV
More stable
Better BA
Less toxicity
Examples
Levodopa - Dopamine
Enalapril - Enalaprilat
Dipivefrine - Epinephrine
TYPES
BIOTRANSFORMATION REACTIONS - 2 TYPES
Phase I / Non synthetic / Functionalization
A functional group is generated
Metabolite – active or inactive
Phase II / Synthetic / Conjugation
An endogenous radical is conjugated
Metabolite is usually inactive
Phase I Reactions
Oxidation
Reduction
Hydrolysis
Cyclization
Decyclization
Phase II Reactions
Glucuronide conjugation
Acetylation
Methylation
Sulfate conjugation
Glycine conjugation
Glutathione conjugation
Ribonucleotide / Ribonucleoside synthesis
OXIDATION
Addition of Oxygen / negatively charged
radical or removal of Hydrogen / Positively
charged radical
Oxidation is the main process of metabolism
Produces unstable intermediates - Epoxides,
Superoxides, Quinones
Oxidation – 9 types
1.OXIDATION AT NITROGEN ATOM
Chlorpheniramine
Dapsone
Meperidine
2.OXIDATION AT SULPHUR ATOM
Chlorpromazine
Chloramphenicol
ALIPHATIC HYDROXYLATION
Hydroxyl group added to drug
Salicylic acid to Gentisic acid
Ibuprofen
Tolbutamide, Chlorpropamide,
AROMATIC HYDROXYLATION
Phenytoin
Phenobarbitone
Propranolol
DEALKYLATON AT OXYGEN ATOM
Phenacetin to Paracetamol
6.DEALKYLATON AT NITROGEN ATOM
Amitriptyline to Nortriptyline
DEALKYLATON AT SULPHUR ATOM
6Methyl thiopurine to Mercaptopurine
8.OXIDATIVE DEAMINATION
Amphetamine
9.DESULFURATION
Parathion to Paraoxon
Main enzymes are the Oxygenases –
MICROSOMAL MONOOXYGENASES in liver
( Cytochrome p450/CYP )- drugs
CYP( 450)s require NADPH & Oxygen
Drug Metabolizing Enzymes – 2 types
Microsomal – CYP 450, UDPGT
Non microsomal – Flavoprotein
oxidases,esterases…
NONMICROSOMAL OXIDATION
Mitochondrial enzymes -MAO—Oxidative
deamination of Adrenaline,5HT,Tyramine
Cytoplasmic enzymes – Dehydrogenases
Alcohol Oxidation to Acetaldehyde &
Acetic Acid
Plasma oxidative enzymes- Histaminase,
Xanthine oxidas
b) REDUCTION
Addition of Hydrogen / positively charged
radical or
removal of Oxygen / negatively charged radical
MICROSOMAL REDUCTION by Monooxygenases
need NADPH & cytochrome c reductase.
A.NITRO Reduction-
Chloramphenicol to aryl amine metabolite
B.KETO Reduction –
Cortisone to Hydrocortisone,
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
AZO Reduction
Prontosil to Sulfanilamide
NON MICROSOMAL REDUCTION
Chloral hydrate to Trichloro ethanol
d) CYCLIZATION
Formation of ring structure from a straight
chain compound. Eg: Proguanil
e) DE CYCLIZATION
Ring structure opened
Phenytoin, Barbiturates
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
7 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
ACETYLATION
Drugs with Amino or Hydrazine
groups - INH, PAS, Hydralazine, Sulfonamides
Procainamide, Dapsone. ( Code - SHIP)
N Acetyl 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
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
Endogenous substance- Cysteine, Methionine
7. RIBONUCLEOTIDE /RIBONUCLEOSIDE
SYNTHESIS
Action of Purine & Pyrimidine antimetabolites
6 Mercaptopurine
INHIBITION OF DRUG METABOLISM
One drug can inhibit the metabolism of another
drug
↑ in circulating levels of slowly metabolised drug
Prolongation or potentiation of its effects
Consequences
Precipitate toxicity of the object drug.
can be therapeutically beneficial. Eg: Aversion of
alcohol with disulfiram,
Reversal of Skeletal Muscle paralysis of d-tc by
Neostigmine
Valproate
Ketoconazole
Cimetidine
Ciprofloxacin
Erythromycin
INH
MICROSOMAL ENZYME INDUCTION
Drugs, insecticides, carcinogens will induce
the synthesis of microsomal enzyme proteins
Accelerated metabolism and reduced
pharmacological response
Consequences
Drug- drug interactions
Can lead to toxicity. Eg: Alcoholics more
prone to hepatotoxicity of paracetamol due to↑
production of NABQI , Pptn of a/c intermittent
porphyria by barbiturate
Therapeutic benefit. Eg: To treat neonatal
jaundice
Decreased duration of action. Eg: OCP failure
Griseofulvin
Phenytoin, Primidone
Rifampicin
Smoking
Carbamazepine
Phenobarbitone
 Metabolism - major
1) Phase I and II reactions
2) Function: change a lipid soluble to more
water soluble molecule to excrete in kidney
3) Possibility of active metabolites with
same or different properties as parent
molecule
 Biliary Secretion – active transport, 4 categories
Portal circulation
Liver
gall bladder
Gut
Bile
duct
Drug
Biotransformation;
glucuronide produced
Bile formation
Hydrolysis by
beta glucuronidase
Liver enzymes inactivate some drug molecules
First pass effect (induces enzyme activity)
P450 activity is genetically determined:
Some persons lack such activity  leads to
higher drug plasma levels (adverse actions)
Some persons have high levels  leads to lower
plasma levels (and reduced drug action)
Other drugs can interact with the P450 systems
Either induce activity (apparent tolerance)
Inactivate an enzyme system
Enzyme (CYP) Substrate Inhibitor Inducer
1A2 Clozapine, haloperidol Cimetidine Tobacco smoke
2B6 Bupropion Thiotepa Phenobarbital
2C19 Citalopram Fluoxetine Prednisone
2C9 Fluoxetine Paroxetine Secobarbital
2D6 Most ADs, Aps CPZ, ranitidine Dexamethasone
2E1 Gas anesthetics Disulfiram Ethanol
3A4,5,7 Alprazolam Grapefruit juiceGlucocorticoid
 Multiple CYP gene families have been identified in
humans, and the categories are based upon protein
sequence homology
 Most of the drug metabolizing enzymes are in CYP 1,
2, & 3 families .
 CYPs have molecular weights of 45-60 kDa.
 Frequently, two or more enzymes can catalyze the
same type of oxidation, indicating redundant and
broad substrate specificity.
 CYP3A4 is very common to the metabolism of many
drugs; its presence in the GI tract is responsible for
poor oral availabilty of many drugs
 Monoamine Oxidase (MAO), Diamine Oxidase (DAO) - MAO
(mitochondrial) oxidatively deaminates endogenous
substrates including neurotransmitters (dopamine,
serotonin, norepinephrine, epinephrine); drugs designed to
inhibit MAO used to affect balance of CNS
neurotransmitters (L-DOPA); MPTP converted to toxin
MPP+ through MAO-B. DAO substrates include histamine
and polyamines.
 Alcohol & Aldehyde Dehydrogenase - non-specific enzymes
found in soluble fraction of liver; ethanol metabolism
 Xanthine Oxidase - converts hypoxanthine to xanthine, and
then to uric acid. Drug substrates include theophylline, 6-
mercaptopurine. Allopurinol is substrate and inhibitor of
xanthine oxidase; delays metabolism of other substrates;
effective for treatment of gout.
~60% ~35%
CYP2E1*
CYP1A2
CYP3A11
NAPQI
N-acetyl-p-benzoquinone imine
*induced by ethanol, isoniazid
Protein adducts,
Oxidative stress
Toxicity
HN
COCH3
OH
HN
COCH3
O
SO3H
HN
COCH3
O
O CO2H
OH
OH
HO
N
O
COCH3
Classs drug metabolism

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Classs drug metabolism

  • 1. Dr. RAGHU PRASADA M S MBBS,MD ASSOCIATE PROFESSOR DEPT. OF PHARMACOLOGY SSIMS & RC. 1
  • 2. It is chemical alteration of drug in the body, wherein Non polar lipid soluble compounds are made polar lipid insoluble, so that they are easily excreted. Drugs which do not undergo biotransformation – Streptomycin, neostigmine….(highly polar drugs) Primary site – Liver Others – Kidney, Intestine, Lungs, Plasma
  • 3. Drug Biotransformation –convert lipophilic / hydrophobic drug (to enter cells) to hydrophilic metabolites. Advantages Termination of drug action - (↓ toxicity) Reduced lipophilicity. Renal / biliary excretion ↑ - (↓renal reabs)
  • 4. Metabolic changes by Enzymes ( Microsomal, Cytoplasmic, Mitochondrial) Spontaneous Molecular rearrangement – HOFMANN ELIMINATION Excreted unchanged (highly polar drugs) - Aminoglycosides, Methotrexate, Neostigmine
  • 5. A) Drug inactivation - inactive or less active Propranolol, Pentobarbitone, Morphine, Chloramphenicol, Paracetamol, Ibuprofen, lignocaine B) Active drug to Active metabolite- active metabolite Effect is due to parent drug and its active metabolite
  • 6. Phenacetin - Paracetamol Phenyl butazone - Oxyphenbutazone Primidone - Phenobarbitone Diazepam - Oxazepam Digitoxin - Digoxin Amitriptyline - Nortriptyline Codeine - Morphine Spironolactone - Canrenone Allopurinol - Alloxanthine Cefotaxime - Des acetyl cefotaxime Morphine - Morphine 6 glucuronide
  • 7. C) Inactive drug (Prodrug) - Active drug Prodrugs are inactive drugs which need BT in the body to form active metabolites. ADV More stable Better BA Less toxicity Examples Levodopa - Dopamine Enalapril - Enalaprilat Dipivefrine - Epinephrine
  • 8. TYPES BIOTRANSFORMATION REACTIONS - 2 TYPES Phase I / Non synthetic / Functionalization A functional group is generated Metabolite – active or inactive Phase II / Synthetic / Conjugation An endogenous radical is conjugated Metabolite is usually inactive
  • 10. Phase II Reactions Glucuronide conjugation Acetylation Methylation Sulfate conjugation Glycine conjugation Glutathione conjugation Ribonucleotide / Ribonucleoside synthesis
  • 11. OXIDATION Addition of Oxygen / negatively charged radical or removal of Hydrogen / Positively charged radical Oxidation is the main process of metabolism Produces unstable intermediates - Epoxides, Superoxides, Quinones Oxidation – 9 types
  • 12. 1.OXIDATION AT NITROGEN ATOM Chlorpheniramine Dapsone Meperidine 2.OXIDATION AT SULPHUR ATOM Chlorpromazine Chloramphenicol
  • 13. ALIPHATIC HYDROXYLATION Hydroxyl group added to drug Salicylic acid to Gentisic acid Ibuprofen Tolbutamide, Chlorpropamide, AROMATIC HYDROXYLATION Phenytoin Phenobarbitone Propranolol
  • 14. DEALKYLATON AT OXYGEN ATOM Phenacetin to Paracetamol 6.DEALKYLATON AT NITROGEN ATOM Amitriptyline to Nortriptyline DEALKYLATON AT SULPHUR ATOM 6Methyl thiopurine to Mercaptopurine 8.OXIDATIVE DEAMINATION Amphetamine 9.DESULFURATION Parathion to Paraoxon
  • 15. Main enzymes are the Oxygenases – MICROSOMAL MONOOXYGENASES in liver ( Cytochrome p450/CYP )- drugs CYP( 450)s require NADPH & Oxygen Drug Metabolizing Enzymes – 2 types Microsomal – CYP 450, UDPGT Non microsomal – Flavoprotein oxidases,esterases…
  • 16. NONMICROSOMAL OXIDATION Mitochondrial enzymes -MAO—Oxidative deamination of Adrenaline,5HT,Tyramine Cytoplasmic enzymes – Dehydrogenases Alcohol Oxidation to Acetaldehyde & Acetic Acid Plasma oxidative enzymes- Histaminase, Xanthine oxidas
  • 17. b) REDUCTION Addition of Hydrogen / positively charged radical or removal of Oxygen / negatively charged radical MICROSOMAL REDUCTION by Monooxygenases need NADPH & cytochrome c reductase. A.NITRO Reduction- Chloramphenicol to aryl amine metabolite B.KETO Reduction – Cortisone to Hydrocortisone,
  • 18. 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
  • 19. AZO Reduction Prontosil to Sulfanilamide NON MICROSOMAL REDUCTION Chloral hydrate to Trichloro ethanol
  • 20. d) CYCLIZATION Formation of ring structure from a straight chain compound. Eg: Proguanil e) DE CYCLIZATION Ring structure opened Phenytoin, Barbiturates
  • 21. 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
  • 22. Conjugates-hydrophilic, ionized, ↑mol.weight, Inactive Excreted in urine/ bile/ faeces. Phase II- need energy 7 types of reactions
  • 23. 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
  • 24. ↑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
  • 25. ACETYLATION Drugs with Amino or Hydrazine groups - INH, PAS, Hydralazine, Sulfonamides Procainamide, Dapsone. ( Code - SHIP) N Acetyl transferase Acetyl CoA Genetic polymorphism Acetylation- Rapid / Slow
  • 26. 3. CONJUGATION WITH SULFATE Drug groups-Amino, Hydroxyl Cytoplasmic Enzymes - Sulfotransferases / Sulfokinases. Methyl dopa, Steroids, Chloramphenicol, Warfarin
  • 27. 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
  • 28. 6. METHYLATION Drugs with Amino & Phenol groups Histamine, Adrenaline, Nicotinic acid, Dopamine, Methyl dopa, Captopril Enzyme- Methyl transferase Endogenous substance- Cysteine, Methionine
  • 29. 7. RIBONUCLEOTIDE /RIBONUCLEOSIDE SYNTHESIS Action of Purine & Pyrimidine antimetabolites 6 Mercaptopurine
  • 30. INHIBITION OF DRUG METABOLISM One drug can inhibit the metabolism of another drug ↑ in circulating levels of slowly metabolised drug Prolongation or potentiation of its effects Consequences Precipitate toxicity of the object drug. can be therapeutically beneficial. Eg: Aversion of alcohol with disulfiram, Reversal of Skeletal Muscle paralysis of d-tc by Neostigmine
  • 32. MICROSOMAL ENZYME INDUCTION Drugs, insecticides, carcinogens will induce the synthesis of microsomal enzyme proteins Accelerated metabolism and reduced pharmacological response Consequences Drug- drug interactions Can lead to toxicity. Eg: Alcoholics more prone to hepatotoxicity of paracetamol due to↑ production of NABQI , Pptn of a/c intermittent porphyria by barbiturate
  • 33. Therapeutic benefit. Eg: To treat neonatal jaundice Decreased duration of action. Eg: OCP failure Griseofulvin Phenytoin, Primidone Rifampicin Smoking Carbamazepine Phenobarbitone
  • 34.  Metabolism - major 1) Phase I and II reactions 2) Function: change a lipid soluble to more water soluble molecule to excrete in kidney 3) Possibility of active metabolites with same or different properties as parent molecule  Biliary Secretion – active transport, 4 categories
  • 35. Portal circulation Liver gall bladder Gut Bile duct Drug Biotransformation; glucuronide produced Bile formation Hydrolysis by beta glucuronidase
  • 36. Liver enzymes inactivate some drug molecules First pass effect (induces enzyme activity) P450 activity is genetically determined: Some persons lack such activity  leads to higher drug plasma levels (adverse actions) Some persons have high levels  leads to lower plasma levels (and reduced drug action) Other drugs can interact with the P450 systems Either induce activity (apparent tolerance) Inactivate an enzyme system
  • 37. Enzyme (CYP) Substrate Inhibitor Inducer 1A2 Clozapine, haloperidol Cimetidine Tobacco smoke 2B6 Bupropion Thiotepa Phenobarbital 2C19 Citalopram Fluoxetine Prednisone 2C9 Fluoxetine Paroxetine Secobarbital 2D6 Most ADs, Aps CPZ, ranitidine Dexamethasone 2E1 Gas anesthetics Disulfiram Ethanol 3A4,5,7 Alprazolam Grapefruit juiceGlucocorticoid
  • 38.  Multiple CYP gene families have been identified in humans, and the categories are based upon protein sequence homology  Most of the drug metabolizing enzymes are in CYP 1, 2, & 3 families .  CYPs have molecular weights of 45-60 kDa.  Frequently, two or more enzymes can catalyze the same type of oxidation, indicating redundant and broad substrate specificity.  CYP3A4 is very common to the metabolism of many drugs; its presence in the GI tract is responsible for poor oral availabilty of many drugs
  • 39.  Monoamine Oxidase (MAO), Diamine Oxidase (DAO) - MAO (mitochondrial) oxidatively deaminates endogenous substrates including neurotransmitters (dopamine, serotonin, norepinephrine, epinephrine); drugs designed to inhibit MAO used to affect balance of CNS neurotransmitters (L-DOPA); MPTP converted to toxin MPP+ through MAO-B. DAO substrates include histamine and polyamines.  Alcohol & Aldehyde Dehydrogenase - non-specific enzymes found in soluble fraction of liver; ethanol metabolism  Xanthine Oxidase - converts hypoxanthine to xanthine, and then to uric acid. Drug substrates include theophylline, 6- mercaptopurine. Allopurinol is substrate and inhibitor of xanthine oxidase; delays metabolism of other substrates; effective for treatment of gout.
  • 40. ~60% ~35% CYP2E1* CYP1A2 CYP3A11 NAPQI N-acetyl-p-benzoquinone imine *induced by ethanol, isoniazid Protein adducts, Oxidative stress Toxicity HN COCH3 OH HN COCH3 O SO3H HN COCH3 O O CO2H OH OH HO N O COCH3