Drug Metabolism

Presenter : -
Rinku Kundu (B.pharm)

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 Outline
• Introduction
• Phases of Metabolism
• Phase I Metabolism
• Cytochrome P family
• Phase II Metabolism
• Factors affecting Biotransformation

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 Introduction
• Biotransformation: Chemical alteration of
the drug in body that converts nonpolar
or lipid soluble compounds to polar or
lipid insoluble compounds
• Consequences of biotransformation
• Active drug  Inactive metabolite :
Pentobarbitone, Morphine, Chloramphenicol
• Active drug  Active metabolite: Phenacetin
• Inactive drug  active metabolite: Levodopa

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 Phases of Metabolism
• Phase I
• Functionalization reactions
• Converts the parent drug to a more polar
metabolite by introducing or unmasking a
functional group (-OH, -NH2, -SH).
• Phase II
• Conjugation reactions
• Subsequent reaction in which a covalent
linkage is formed between a functional
group
on the parent compound or Phase I
metabolite and an endogenous substrate
such
as glucuronic acid, sulfate, acetate, or an
amino acid
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 Phases of Metabolism
Hydrolytic Reactions
 Esters, amides, epoxides Oxidation
and  Aromatic moieties, Olefins
arene oxides by epoxide hydrase  Benzylic & allylic C atoms
and a-C of C=O and C=N
Phase II -  At aliphatic and alicyclic C
Phase I -  C-Heteroatom system
Conjugation
Functionalization  C-N (N-dealkylation, N-
oxide formation, N-
hydroxylation)
 C-O (O-dealkylation)
Drug  S-dealkylation
Metabolism  S-oxidation, desulfuration
 Oxidation of alcohols and
aldehydes,
 Conjugation Miscellaneous
 Glucuronic acid Reduction
 Sulfate, Glycine and other AA  Aldehydes and ketones
 Glutathione or mercapturic acid  Nitro and azo
 Acetylation, Methylation  Miscellaneous

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Phase I / Non Synthetic Reactions
Oxidation
• Addition of oxygen/ negatively charged radical
or removal of hydrogen/ positvely charged
radical.
• Reactions are carried out by group of mono-
oxygenases in the liver.

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 Cytochrome P450 enzymes
• Monooxygenase enzyme family
• Major catalyst: Drug and endogenous
compound oxidations in liver, kidney, G.I. tract,
skin and lungs.
• Location: smooth endoplasmic reticulum.
• The reductase serves as the electron source for
the oxidative reaction cycle

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 Cytochrome P
family
• Multiple CYP gene families have been identified in
humans, and the categoriezed based on protein
sequence homology
• Most of the drug metabolizing enzymes are in CYP
1, 2, & 3 families .
• Frequently, two or more enzymes can catalyze the
same type of oxidation, indicating redundant and
broad substrate specificity.

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 Reduction
• Converse of oxidation
• Addition of Hydrogen / positively charged radical
or removal of Oxygen / negatively charged
radical
• Drugs primarily reduced are chloralhydrate,
chloramphenicol, halothane.

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 MICROSOMAL REDUCTION

A.NITRO Reduction- RNo2 RNH2

 Chloramphenicol to aryl amine metabolite

O OH
B.KETO Reduction - R-C-R1 R-CH-R1
 Cortisone to Hydrocortisone,
C. AZO Reduction
Prontosil to Sulfanilamide

NON MICROSOMAL REDUCTION

 Chloral hydrate to Trichloro ethanol

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
 Cyclization and Decyclization

• Cyclization
• Formation of ring structure from a straight
chain compound
• E.g. Proguanil

• Decyclization
• Opening up of ring structure of the cyclic
drug molecule
• E.g. Barbiturates, Phenytoin.

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 PHASE II REACTIONS
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
 6 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
 2. ACETYLATION
 Drugs with Amino or Hydrazine
groups - INH,PAS,Hydralazine,Sulfonamides
Procainamide,Dapsone.

 R-NH2 N Acetyl R-NHCOCH3

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
4. 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

RIBONUCLEOTIDE /RIBONUCLEOSIDE
SYNTHESIS

 Action of Purine & Pyrimidine antimetabolites

 6 Mercaptopurine
Thank You
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