1. SREE DATTHA INSTITUTE OF PHARMACY
Sheriguda, Ibrahimpatnam, Telangana 5010510
Presented by:
Khaja Majeed Uddin 16U21R0016
Under the guidance of:
Asst. Professor: Mrs. Naga Chandrika
SREE DATTHA INSTITUTE OF PHARMACY
SREE DATTHA INSTITUTE OF PHARMACY 1
3. Introduction
Biotransformation:
Metabolism or biotransformation is the process of transformation of chemical entity
(xenobiotics ) into entirely different chemically active or inactive metabolite inside the living
body by a series of enzyme catalyzed reaction and results in their elimination.
The pathways of drug metabolisms are categorized into phase I and phase II reactions.
1. Phase I (Functionalization)Reaction:
In these phase the drug undergoes oxidative, reductive and
hydrolysis reactions. The purpose of these reactions is to produce a more polar and easily
excretable water soluble metabolite.
Example: Reduction of ketones and aldehydes to alcohol, oxidation of alcohols to acids.
SREE DATTHA INSTITUTE OF PHARMACY 3
4. 2.Phase II(Conjugation)Reactions:
These are the enzymatic synthesis reactions which attaches small
polar and ionizable endogenous compounds such as sulphate, methyl ,glucuronic acid, glycine
and other amino acids to the functional group of the intermediates obtained in phase I
reactions or to the parent drug to form water soluble and easily excretable conjugated
product.
Most of the drugs undergo phase I and phase II reactions subsequentially and thus
complement each other in detoxification and elimination of the drugs
SREE DATTHA INSTITUTE OF PHARMACY 4
7. Conjugation Reaction:
The term conjugation refers to combination or attachment of two substances. Conjugation
reaction are important xenobiotic biotransformation reactions as they result in metabolites that are
more water soluble, readily excretable, pharmacologically inactive and non toxic.
Glucuronidation Reactions
i. O-glucuronidation : Ex : Morphine, benzoic acid
ii. N-glucuronidation : Ex : Desipramine
iii. S-glucuronidation : Ex : Thiopental
iv. C-glucuronidation : Ex : Phenylbutazone
SREE DATTHA INSTITUTE OF PHARMACY 7
.
8. Sulphation Reaction
Amino Acid Conjugation Ex: Phenylacetic acid
Glutathione conjugation Ex : Ethacrynic acid, azathioprine
Acetylation Ex : p-amino salicylic acid (PAS)
Methylation
i. O-methylation : Ex : Morphine
ii. N-methylation : Ex : Norephedrine
iii. S-methylation : Ex : 6-Mercaptopurine
SREE DATTHA INSTITUTE OF PHARMACY 8
9. SREE DATTHA INSTITUTE OF PHARMACY 9
Conjugation
reaction
Conjugating
agent
Functional
group involved
(X)
Catalytic
enzyme
involved
High energy
intermediate
formed
Glucuronidatio
n
(occurs in
microsomes)
glucuronic acid -NH2, -OH,
-NR2, -SH,
--COOH
UDP-glucuronyl
transferase
(liver).
Uridine
diphosphate
glucuronic acid.
(UDPGA)
Glucuronidation is a process of addition of glucuronic acid moiety to a
compound. Glucuronidations reaction is the most common among phase II
reactions. Large amount of conjugates found in urine and bile are the
products of glucuronidation.
10. Different forms of glucuronidation conjugation reactions are as follows :
SREE DATTHA INSTITUTE OF PHARMACY 10
Conjugation reaction Functional group involved
(X)
Mechanism
1. O-glucuronidation
Involving hydroxyl compounds
Ex: Morphine, Acetaminophem.
Involving carboxyl compounds
Ex: Benzoic acid, salicylic acid
-OH (phenolic, alcoholic, enols
etc)
-COOH
(aryl and aryl alkyl acids)
UDP glucuronyl
UDPGA +ROH
transferase
R--O-glucoronic acid + UDP.
UDP-glucuronyl
UDPGA +R-COOH
transferase
R-CO O –glucuronic acid+UDP
2. N-Glucuronidation
Ex: Benzoic acid, salicylic acid,
Naproxen
-NH2, -NR2
( aryl, alkyl amines, amides,
sulfonamides).
UDPG transferase
UDPGA + R-COOH
R-N-H-glucuronic acid + UDP
11. 3. S- glucuronidation
Ex : Thiophenol, Methimazole.
4. C-glucuronidation
Ex : Phenylbutazone, sulfinpyrazone.
-SH (Thiols)
C H
UDGP transferase
UDPGA + R – SH
R-S- glucuronic acid +UDP
UDPG transferase
UDPGA + R C H
R – C - glucuronic acid + UDP
( C- glucuronide )
SREE DATTHA INSTITUTE OF PHARMACY 11
12. • Sulphation is the process of addition of a sulphate group to a compound. IT
occurs rarely when compared to glucuronidation due to limited availability of
sulphate ion in the body. Addition of sulphate group enhances the solubility of
the conjugate making it inactive and readily excretable. This is due to the
ionizable property of sulphate conjugate ( pKa of sulphonate is 1-2 ).
SREE DATTHA INSTITUTE OF PHARMACY 12
Conjugation
reaction.
Sulphation
Conjugating agent
Suphate
Function groups
involved (X)
-OH, -NH2
Catalytic enzyme
involved
Sulphatransferase
High energy
metabolite formed
3- Phospho-
Adenosine- 5
phopsphate
13. SREE DATTHA INSTITUTE OF PHARMACY 13
Conjugation
reaction
Conjugating
agents
Functional group
involved (X)
Catalytic enzyme
involved
High energy
intermediate
formed
ᾳ- amino acid
conjugation Glycine, glutamine -COOH N- acyl transferase Acyl CoA
Amino acid like glycine and glutamine are used by humans and other mammals
to conjugate carboxylic acids, particularly aromatic acids and aryl alkyl acids. The
process takes place in the mitochondria of liver and kidney cells.
14. • Glutathione conjugation is an important pathway in the detoxification of
chemically reactive electrophilic moieties. Glutathione is a tripeptide found in
most of the tissues. It is highly reactive nucleophile due to the presence of thiol
( -SH ) group in its structure.
SREE DATTHA INSTITUTE OF PHARMACY 14
Conjugation reaction Conjugating agent Functionals groups
involved (X)
Catalytic enzyme
involved
Glutathione
Conjugation
Glutathione Aryl, alkyl halides,
arene oxides, aliphalic
epoxides, sulphates,
etc..
Glutathione -5-
transferase ( GST )
16. Acetylation is the process of addition of an acetyl ( CH3CO ) group to
substrate, to form amides. Its is an important route of metabolic
biotransformation for drugs containing primary aromatic amines,
sulphonamides, hydrazines, hydrazides and primary aliphatic amines
SREE DATTHA INSTITUTE OF PHARMACY 16
Conjugation
reaction
Conjugating
agent
Functional
group
involved (X)
Catalytic
enzyme
involved
High energy
intermediate formed
Acetylation reaction Acetyl CoA -OH, _NH2 N – acetyl
transferases
Acetyl CoA
17. Methylation is the process of addition of methyl group to a compound and is
catalyzed by the enzyme methyl transferase
Methylation constitutes a minor pathway in the conjugation of drugs and
xenobiotics but plays a major role in the biosynthesis of endogenous compound
like epinephrine and melatonin and in the activation of endogenous amines such
as dopamine, norepinephrine, serotonin, N-acetyl serotonin, histamine etc..
SREE DATTHA INSTITUTE OF PHARMACY 17
19. SREE DATTHA INSTITUTE OF PHARMACY 19
Conjugation reaction Functional groups
involved (X)
Formation of conjugate /
Mechanism
1. O- methylation
Ex: Morphine -OH ( phenolic ,alcoholic)
SAM + R-OH
methyl transferase
R – O – CH3 + S- -adenosyl
homocysteine
2 . N – methylation
Ex: Norepinephrine,
normorphine, nicotine..
-NH2,
Heterocyclic N
SAM + R- NH2
methyl transferase
R – N – CH3+ S-adenosyl
homocysteine
3. S –methylation
Ex: 6-mercaptopurine -SH (Thiols)
SAM + R – SH
methyl transferase
R- S – CH3 + S- adenosyl
homocysteine
20. SREE DATTHA INSTITUTE OF PHARMACY 20
Reference:
Author Name: D.M. BRAHMAKAR, SUNIL B.
JAISWAL
Book Name: Biopharmaceutics and
Pharmacokinetics A Treatise
