drug metabolism

1. Drug Metabolism
Mr. Jacob Martin
1st year mpharm
Department of pharmacology
Shree devi college of pharmacy manglore

2. DEFINITIONS
 Metabolism: refers to the entire network of chemical processes
involved in maintaining life.
 Energy metabolism: the ways that the body obtains and spends
energy from food.

3. DRUG METABOLISM
Metabolism

4. SITES OF DRUG METABOLISM
Metabolism occurs in many tissues
E.g. brain, kidney, lung, plasma, intestine.

5. Oral
Administration
Intestines
Liver
Intravenous
Administration

6. Anabolism: The building of compounds from small molecules
into larger ones. Energy is used for this process to take place.
Catabolism: The breakdown of molecules into smaller units.
Energy is released in this process.
 Ex: Glucose catabolism results in the release of CO2 and H2O

7. ATP(ADENOSINE TRIPHOSPHATE):
 The main energy source of cells.
 Used for muscular contractions, enzyme activity, etc.
 Catabolism results in the production of many ATP molecules:
energy.
 Used by the body when energy is needed.
 Hydrolysis breaks the bonds in ATP, thus releasing energy.

8. METABOLIC EFFICIENCY:
 Food energy is converted to ATP with approximately 50% efficiency.
 The other 50% is released as heat.

9. HOW IS ENERGY PRODUCED?
Three stages:
1. Proteins, Carbohydrates and Fats are broken down during digestion
and absorption into smaller units: AAs, monosaccharides and fatty
acids.
2. These smaller compounds are further broken down into 2-carbon
compounds.
3. Compounds are degraded into CO2 and H20.

10. HELPERS IN REACTIONS:
 Enzymes: proteins that facilitate chemical reactions without being
changed in the process; protein catalysts.
 Coenzymes: assist enzymes in their activities.

11. Consequence
of metabolism
Equel inactivation
Increased
activity

12. CONSEQUENCES OF METABOLISM
 The metabolite may have…
1) . No or reduced activity (inactivation)
Most drugs and their active metabolite are rendered
inactive.
Examples- Phenobarbitone Morphine
Chloramphenicol Propranolol.

13. The metabolite may have…
2) . Equal activity to the drug
Many drugs have been found to be partially converted
to active metabolite.
Examples-

14. The metabolite may have…
3) . Increased activity (Prodrug)
Features:
 Toxic properties not seen with the parent drug
 Stable drug
 Better PK profile and bioavailability.

15. FIRST PASS EFFECT
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.

17. MICROSOMAL
ENZYMES
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)

18. CYTOCHROME P450
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:

19. CYP 450 SYSTEM
DEFINITIONS
 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

20. CYTOCHROME P450 EXPRESSION
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

21. CYP2D6
Family
Sub-Family Individual Gene

22. ENZYME CHARACTERISTICS
% OF DRUGS METABOLISED BY ENZYME
3A4 60%
2D6 25%
1A2 15%
2C9 Small no. but significant interactions
2C19 Small no. but significant interactions
 2E1 ?

23. CYTOCHROME P450 EXPRESSION
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

24. NON-
MICROSOMAL
ENZYMES
 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

25. NON –ENZYMATIC
BIO-
TRANSFORMATION
Hoffman’s Elimination
Example: some drugs like atracurium
(skeletal muscle relaxant) are
metabolized in plasma through
molecular rearrangement without
involvement of enzyme action.

26. BIOTRANSFORMATION REACTIONS

27. biotransfor
mation
Phase-1
(non
synthetic)
Phase-2
(synthetic)
Oxidation
Reduction
Hydrolysis
Cyclization
Decyclization
 Glucuronide conjuction
 Acetylation
 Methylation
 Sulfate conjugation
 Glycine conjugation
 Gutathione conjugation

30. COMPARING PHASE I & PHASE II
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

31. PHASE I REACTIONS: OXIDATION
Addition of oxygen (-ve charged radical) or
removal hydrogen (+ve ).
Reactions
Microsomal oxidation
• Hydroxylation
(Phenobarbitone to
• Oxygenation
• Deamination
• Dealkylation
Non Microsomal oxidation
• Mitochondrial oxidation
(Epinephrine by MAO)
• Cytoplasmic oxidation
(alcohol by alcohol dehydrogenase)
• Oxidative deamination
(Histamine)

32. PHASE I: REDUCTIONS
Azo reduction (Microsomal)
eg: prontosil to sulfanilamide
Carbonyl reduction (Non microsomal)
Alcohol dehydrogenase (ADH)
Chloral hydrate is reduced to trichlorothanol

33. PHASE I: HYDROLYSIS
Carboxyesterases (Non microsomal)
Hydrolysis of esters : procaine to PABA by
plasma cholineesterases

34. PHASE II: CONJUGATIONS
 MICROSOMAL
 Glucuronide conjugation
 NON-MICROSOMAL
 N acetyl conjugation
 Sulfate conjugation
 Methyl conjugation
Glutathione
conjugation

35. 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 :

36. PHASE II : NON-MICROSOMAL CONJUGATION
Conjugation Reaction Enzyme Examples
N acetyl conjugation N-acetyltransferase Dapsone,
Sulphonamides,
Histamine
Sulfate conjugation Sulfotransferase Paracetamol,
Corticosteroids
Methyl conjugation
(minor Pathway)
Transmethylase Catecholamines

37. ENZYME INDUCTION

38. ENZYME INDUCTION
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

39. ENZYME INDUCTION
Enzyme inducers Enzymes induced substrates
Phenobarbitone
Phenytoin
carbamazepine
CYP3A4 Midazolam
Macrolides
Calcium channel
blockers
Rifampicin
Phenobarbitone
CYP3A4 &
CYP2C9
Oral
contraceptives
Warrfarin

40. SOME ENZYME INDUCERS
 Barbiturates (3A)
 Carbamazepine
(2C19, 3A)
 Phenytoin (3A)
 Rifampicin
(2C19, 2C9, 3A)
 St Johns Wort (3A)
 Ethanol (2E1)
 Troglitazone (3A)
 Tobacco (1A2)
 Omeprazole (1A2)
 Nevirapine (3A)

41. CLINICAL IMPORTANCE
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

42. ENZYME INHIBITION
 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

43. SOME ENZYME INHIBITORS
 Cimetidine
 Fluoxetine
 Erythromycin
 Chloramphenicol

44. REFERENCE
 KD THRIPATI
 YOUTUBE- PHARMACY FUN
 SLIDESHARE
 WIKIPEDIA