drug metabolism, phase I metabolism, biotransformation, Xenobiotics- substances foreign to body Non polar lipid soluble compounds are made polar lipid insoluble, so that they are easily excreted. Advantages of metabolism Termination of drug action ↓ toxicity Reduced lipophilicity. Renal / biliary excretion ↑ ↑ water solubility ↑ polarity ↑ excretion Loss of phsiological activity Active drug → more active drug Non Active drug → active drug Active drug → inactive drug BIOTRANSFORMATION REACTIONS - 2 TYPES Phase I / Non synthetic / Functionalization A functional group is generated Metabolite – active or inactive Phase II / Synthetic / Conjugation Metabolite is usually inactive BIOTRANSFORMATION REACTIONS - 2 TYPES Phase I / Non synthetic / Functionalization A functional group is generated Metabolite – active or inactive Phase II / Synthetic / Conjugation Metabolite is usually inactive Depending upon nature and localisation of enzymes which catalyse reaction – Microsomal enzymes Non- Microsomal enzymes Oxidation of alcohol ethanol→ acetaldehyde → acetic acid →TCA cycle → CO₂ Eg. chloral hydrate → trichloroacetic acid mefenamic acid → hydroxy methyl derivative ALIPHATIC HYDROXYLATION  Hydroxyl group added to drug RCH2CH3 O RCHOHCH3 Salicylic acid to Gentisic acid Ibuprofen Tolbutamide, Chlorpropamide,

1. DRUG METABOLISM
Lecture by-P riyanka Bindlish
GGSCOP Yamunanagar

2. Metabolism : It is a general term used for
chemical transformation of xenobiotics and
endogenous nutrients (e.g., proteins,
carbohydrates and fats) within or outside the body.
Xenobiotics : These are all chemical substances
that are not nutrient for body (foreign to body) and
which enter the body through ingestion, inhalation
or dermal exposure.
They include :
drugs, industrial
chemicals, plant
and animal toxins, etc.
pesticide
s,
pollutants
,

3. Xenobiotics- substances foreign to body
includes- Drugs, Processed food, Food additives,
Cosmetic products, Environmental pollutants, Agrochemicals,
Phytoallexins (dietary plant toxins)
Biotransformation needed for detoxification & protect the
body from ingested toxins.
INTRODUCTION

4. Definition
• Chemical alteration of drug in the body.
• 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)
• SITES
•Primary site – Liver
•Others – Kidney, Intestine, Lungs, Plasma…

5. Advantages of metabolism
Termination of drug action
↓ toxicity
Reduced lipophilicity.
Renal / biliary excretion ↑
↑ water solubility
↑ polarity
↑ excretion
Loss of phsiological activity
Active drug → more active drug
Non Active drug → active drug
Active drug → inactive drug

6. Absorbed drugs – 3 changes
• Metabolic changes by enzymes
( Microsomal, cytoplasmic, mitochondrial)
• Spontaneous molecular rearrangement –
Hofmann elimination
• Excreted unchanged (highly polar drugs) -
aminoglycosides,methotrexate,neostigmine

7. METABOLISM
Biotransformation/
Phase I
Oxidation
Reduction
Hydrolysis
Conjugation/
Phase II
Biosynthetic reactions
Drug+ sulphate
Acetyl
Methyl
Amino acids
Glucuronic acid

8. TYPES
BIOTRANSFORMATION REACTIONS - 2 TYPES
Phase I / Non synthetic / Functionalization
 A functional group is generated
 Metabolite – active or inactive
Phase II / Synthetic / Conjugation
Metabolite is usually inactive

9. Phase I Reactions
 Oxidation
 Reduction
 Hydrolysis
 Cyclization
 Decyclization

10. Phase II Reactions
 Glucuronide conjugation
 Acetylation
 Methylation
 Sulfate conjugation
 Glycine conjugation
 Glutathione conjugation
 Ribonucleotide / Ribonucleoside synthesis

11. Consequences
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

12. -
-
Phenacetin -
Phenyl butazone -
Primidone
Diazepam
Digitoxin
Imipramine -
Amitriptyline -
Procainamide -
Codeine -
Spironolactone -
Allopurinol -
Cefotaxime -
Morphine -
Paracetamol
Oxyphenbutazone
Phenobarbitone
Desmethyl diazepam
- Digoxin
Desipramine
Nortriptyline
N Acetyl procainamide
Morphine
Canrenone
Alloxanthine
Des acetyl cefotaxime
Morphine 6 glucuronide

13. C) Inactive drug (Prodrug) - Active drug
Prodrugs are inactive drugs which need BT in the
body to form active metabolites.
 ADVANTAGES
 More stable
 Better BA
 Less toxicity
Levodopa
Enalapril
αMethyl dopa
Dipivefrine
- Dopamine
- Enalaprilat
- αMethyl Norepinephrine
- Epinephrine

14. Proguanil
Prednisone
Bacampicillin
Sulfasalazine
Cyclophosphamide
Mercaptopurine
Prontosil
Acyclovir
- Proguanil triazine
- Prednisolone
- Ampicillin
- 5amino salicylic acid
- Aldophosphamide
- Methyl Mercaptopurine
- Sulfanilamide
- Acyclovir triphosphate

15. Depending upon nature and
localisation of enzymes which
catalyse reaction –
•Microsomal enzymes
•Non- Microsomal enzymes

16. Microsomal enzymes: The endoplasmic reticulum
(especially smooth endoplasmic reticulum) of liver and
other tissues contain a large variety of enzymes, together
called microsomal enzymes
(microsomes are minute spherical vesicles derived from
endoplasmic reticulum after disruption of cells by
centrifugation, enzymes present in microsomes are called
microsomal enzymes).
They catalyse glucuronide conjugation, most
oxidative reactions, and some reductive and hydrolytic
reactions.
The monooxygenases, glucuronyl transferase, etc are
important microsomal enzymes.

17. enzymes: Enzymes occurring in
Non-microsomal
Organelles/sites other than endoplasmic reticulum
(Microsomes) are called non-microsomal enzymes.
These are usually present in the cytoplasm, mitochondria, etc.
And occur mainly in the liver, gl tract, plasma and other tissues.

18. Main sites for metabolism
Liver
Blood
Skin
Kidney
Lungs
Mucosa

20. PHASE I REACTIONS
a) OXIDATION
Addition of Oxygen / removal of
Hydrogen
Oxidation is the main process of metabolism

21. Oxidation of alcohol
ethanol→ acetaldehyde → acetic acid →TCA cycle → CO₂
Eg.
chloral hydrate → trichloroacetic acid
mefenamic acid → hydroxy methyl derivative

24. OXIDATION AT NITROGEN ATOM
RNH2 O RNHOH
Chlorpheniramine
Dapsone

25. OXIDATION AT SULPHUR ATOM /
SULPHOXIDATION
R1
SH2
R1
O S=O
R2 R2
Chlorpromazine
Chloramphenicol
Thiobarbiturates
Parathion → paraxon

26. ALIPHATIC HYDROXYLATION
Hydroxyl group added to drug
RCH2CH3 O RCHOHCH3
Salicylic acid to Gentisic acid
Ibuprofen
Tolbutamide, Chlorpropamide,

27. AROMATIC HYDROXYLATION
R- O R- -OH
•Phenytoin
•Phenobarbitone
•Propranolol

28. DEALKYLATON AT OXYGEN ATOM
ROCH3 O ROH + CH2O
Phenacetin to Paracetamol
DEALKYLATON AT NITROGEN ATOM
RNHCH3 O RNH2 + CH2O
Amitriptyline to Nortriptyline

29. DEALKYLATON AT SULPHUR ATOM
RSCH3 O RSH +CH2O
6Methyl thiopurine to Mercaptopurine
RCHNH2 R
OXIDATIVE DEAMINATION
O RCOR +NH
Amphetamine
DESULFURATION
R1 O R1
P=S P=O
R2
R2
Parathion to Paraoxon

30. REDUCTION
• Addition of Hydrogen / removal of Oxygen
A. NITRO Reduction- RNO2 RNH2
• Chloramphenicol to aryl amine metabolite
O
B. KETO Reduction - R-C-R1
OH
R-CH-R1
• Cortisone to Hydrocortisone,

31. C. AZO Reduction
• Prontosil to Sulfanilamide
• Chloral hydrate to Trichloro ethanol,

33. HYDROLYSIS
• Drug is split by reaction with water
Ester + water Esterases Alcohol & Acid
amide → alcohol/ acid/amine
• Non microsomal hydrolysis – Esterases,Amidases &
Peptidases
Atropine to Tropic acid
Aspirin → salicylic acid + acetic acid

36. CYCLIZATION
Formation of ring structure from a straight chain
compound. Eg: Proguanil
DE CYCLIZATION
Ring structure opened
Phenytoin, Barbiturates