Dr. Rahul Kunkulol , Asso. professor, Dept. Of Pharmacology
• The chemical modification of drugs with
the overall goal of getting rid of the drug
• Enzymes are typically involved in
...
Metabolism
• Metabolism occurs in many tissues
• E.g. brain, kidney, lung, plasma, intestine.
Oral
Administration
Intestines
Liver
Intravenous
Administration
• The metabolite may have…
 No or reduced activity (inactivation)
Most drugs and their active metabolite are rendered
ina...
The metabolite may have…
Equal activity to the drug
Many drugs have been found to be partially converted
to active metabo...
The metabolite may have…
Increased activity (Prodrug)
Features:
• Toxic properties not seen with the parent drug
• Stable...
• Biotransformation of drug by liver or gut enzymes
before compound reaches systemic circulation
• Results in lower system...
• Microsomal cytochrome P450,
monooxygenase family of
enzymes, which oxidize drugs.
• Location-smooth endoplasmic
reticulu...
RH + O2+ H++ NADPH ROH + H2O + NADP+
• Microsomal enzyme ranking first among Phase I
enzymes with respect to catalytic ver...
• Substrate:
Drug is metabolised by the enzyme system
• Inducer:
Drug that will increase the synthesis of CYP450
enzymes
•...
• Specific forms of CYP 450 are classified into
• Families designated by numbers…
• Subfamilies designated by letters… bas...
CYP2D6
Family
Sub-Family Individual Gene
• 3A4 60%
• 2D6 25%
• 1A2 15%
• 2C9 Small no. but significant interactions
• 2C19 Small no. but significant interactions
•...
• Variation in levels, activity due to:
•Genetic polymorphism
•Environmental factors:
•Inducers, inhibitors, disease
•Mult...
• Location :
• Cytoplasm, mitochondria of hepatic cells.
• Examples :
• Monoamine oxidases (MAO), Esterases,
Amidases, Tra...
•Hoffman’s Elimination
• Example: some drugs like
atracurium (skeletal muscle
relaxant) are metabolized in
plasma through ...
Enzyme Phase I Phase II
Typesof
reactions
Oxidation
Reduction
Hydrolysis
Conjugations
Increase in
hydrophilicity
Small Lar...
Addition of oxygen (-ve charged radical) or
removal hydrogen (+ve ).
Reactions
Microsomal oxidation
• Hydroxylation
(Pheno...
• Azo reduction (Microsomal)
eg: prontosil to sulfanilamide
• Carbonyl reduction (Non microsomal)
Alcohol dehydrogenase (A...
• Carboxyesterases (Non microsomal)
• Hydrolysis of esters : procaine to PABA by
plasma cholineesterases
• MICROSOMAL
Glucuronide
conjugation
• NON-MICROSOMAL
N acetyl conjugation
Sulfate conjugation
Methyl conjugation
Glu...
Phase II: Glucuronide Conjugations
• Parent drug or their phase I metabolite that contain
phenolic, alcoholic, carboxylic ...
Conjugation Reaction Enzyme Examples
N acetyl conjugation N-acetyltransferase Dapsone,
Sulphonamides,
Histamine
Sulfate co...
• Several drugs (inducers) induce the growth of
smooth endoplasmic reticulum leading to
enhanced microsomal enzyme activit...
Enzyme inducers Enzymes
induced
substrates
Phenobarbitone
Phenytoin
carbamazepine
CYP3A4 Midazolam
Macrolides
Calcium chan...
• Increased drug metabolism :
• Decreased plasma levels and therapeutic
effects of the substrate ( co administered
drug)
•...
• Often rapid, reversible and relatively short acting.
• E.g. erythromycin and Terfanadine
• Erythromycin causes a rapid i...
• Cimetidine
• Fluoxetine
• Erythromycin
• Chloramphenicol
Drug metabolism : Biotransformation
Drug metabolism : Biotransformation
Drug metabolism : Biotransformation
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Drug metabolism : Biotransformation

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Drug metabolism : Biotransformation

  1. 1. Dr. Rahul Kunkulol , Asso. professor, Dept. Of Pharmacology
  2. 2. • The chemical modification of drugs with the overall goal of getting rid of the drug • Enzymes are typically involved in metabolism
  3. 3. Metabolism
  4. 4. • Metabolism occurs in many tissues • E.g. brain, kidney, lung, plasma, intestine.
  5. 5. Oral Administration Intestines Liver Intravenous Administration
  6. 6. • The metabolite may have…  No or reduced activity (inactivation) Most drugs and their active metabolite are rendered inactive. Examples- Phenobarbitone Morphine Chloramphenicol Propranolol.
  7. 7. The metabolite may have… Equal activity to the drug Many drugs have been found to be partially converted to active metabolite. Examples-
  8. 8. The metabolite may have… Increased activity (Prodrug) Features: • Toxic properties not seen with the parent drug • Stable drug • Better PK profile and bioavailability.
  9. 9. • Biotransformation of drug by liver or gut enzymes before compound reaches systemic circulation • Results in lower systemic bioavailbility of parent compound, diminished therapeutic response. • First pass effect may be bypassed if the drug is administered IV or Sublingually.
  10. 10. • Microsomal cytochrome P450, monooxygenase family of enzymes, which oxidize drugs. • Location-smooth endoplasmic reticulum in Liver, Kidney, intestinal mucosa, and lungs. • They catalyze: • Oxidation, reduction, hydrolysis (phase I reactions) • Glucuronide conjugation (phase II reactions)
  11. 11. RH + O2+ H++ NADPH ROH + H2O + NADP+ • Microsomal enzyme ranking first among Phase I enzymes with respect to catalytic versatility • Heme-containing proteins Complex formed between Fe2+ and CO absorbs light maximally at 450 (447-452nm) Overall reaction proceeds by catalytic cycle:
  12. 12. • Substrate: Drug is metabolised by the enzyme system • Inducer: Drug that will increase the synthesis of CYP450 enzymes • Inhibitor Drug that will decrease the metabolism of a substrate
  13. 13. • Specific forms of CYP 450 are classified into • Families designated by numbers… • Subfamilies designated by letters… based on amino acid sequences • Genes by another number • At least 15 P450 enzymes identified in human liver microsomes
  14. 14. CYP2D6 Family Sub-Family Individual Gene
  15. 15. • 3A4 60% • 2D6 25% • 1A2 15% • 2C9 Small no. but significant interactions • 2C19 Small no. but significant interactions • 2E1 ?
  16. 16. • Variation in levels, activity due to: •Genetic polymorphism •Environmental factors: •Inducers, inhibitors, disease •Multiple P450’s can catalyze same reaction •A single P450 can catalyze multiple pathways
  17. 17. • Location : • Cytoplasm, mitochondria of hepatic cells. • Examples : • Monoamine oxidases (MAO), Esterases, Amidases, Transferases, Conjugages • Reaction catalysed are all Phase II reactions except_?...._____ • These are noninducible • May show genetic variations
  18. 18. •Hoffman’s Elimination • Example: some drugs like atracurium (skeletal muscle relaxant) are metabolized in plasma through molecular rearrangement without involvement of enzyme action.
  19. 19. Enzyme Phase I Phase II Typesof reactions Oxidation Reduction Hydrolysis Conjugations Increase in hydrophilicity Small Large General mechanism Exposes functional group Polar compound added to functional group Consquences May result in metabolic activation Facilitates excretion
  20. 20. Addition of oxygen (-ve charged radical) or removal hydrogen (+ve ). Reactions Microsomal oxidation • Hydroxylation (Phenobarbitone to hydroxyphenobarbitone) • Oxygenation • Deamination • Dealkylation Non Microsomal oxidation • Mitochondrial oxidation (Epinephrine by MAO) • Cytoplasmic oxidation (alcohol by alcohol dehydrogenase) • Oxidative deamination (Histamine)
  21. 21. • Azo reduction (Microsomal) eg: prontosil to sulfanilamide • Carbonyl reduction (Non microsomal) Alcohol dehydrogenase (ADH) • Chloral hydrate is reduced to trichlorothanol
  22. 22. • Carboxyesterases (Non microsomal) • Hydrolysis of esters : procaine to PABA by plasma cholineesterases
  23. 23. • MICROSOMAL Glucuronide conjugation • NON-MICROSOMAL N acetyl conjugation Sulfate conjugation Methyl conjugation Glutathione conjugation
  24. 24. Phase II: Glucuronide Conjugations • Parent drug or their phase I metabolite that contain phenolic, alcoholic, carboxylic group undergoes conjugation with uridine diphospate glucuronic acid (UDPGA). • Catalytic enzyme : UDP –glucuronyl transferase • yield drug- glucuronide conjugates that are polar. Examples :
  25. 25. Conjugation Reaction Enzyme Examples N acetyl conjugation N-acetyltransferase Dapsone, Sulphonamides, Histamine Sulfate conjugation Sulfotransferase Paracetamol, Corticosteroids Methyl conjugation (minor Pathway) Transmethylase Catecholamines
  26. 26. • Several drugs (inducers) induce the growth of smooth endoplasmic reticulum leading to enhanced microsomal enzyme activity Accelerates metabolism Decrease pharmacological response of not only the inducer itself but also of the coadministerd drug (substrate) • Occurs gradually over 1-2 weeks
  27. 27. Enzyme inducers Enzymes induced substrates Phenobarbitone Phenytoin carbamazepine CYP3A4 Midazolam Macrolides Calcium channel blockers Rifampicin Phenobarbitone CYP3A4 & CYP2C9 Oral contraceptives Warrfarin
  28. 28. • Increased drug metabolism : • Decreased plasma levels and therapeutic effects of the substrate ( co administered drug) • Increase drug activity if the metabolite is active • Examples : OC pills , Warfarin (therapeutic failure) • Therapeutic use of enzyme induction
  29. 29. • Often rapid, reversible and relatively short acting. • E.g. erythromycin and Terfanadine • Erythromycin causes a rapid increase in plasma Terfenadine concentration if given concurrently. • Note: Erythromycin is a substrate and an inhibitor of CYP 3A4
  30. 30. • Cimetidine • Fluoxetine • Erythromycin • Chloramphenicol
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