PHASE II: Conjugation Reaction
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CONJUGATION REACTION
Glucuronic acid conjugation
Sulfate conjugation
Conjugation with Glysine, Glutamine, and
other AA
Glutathione or Mercapturic Acid Conjugation
Acetylation
Methylation
CONJUGATION REACTION
 Does not always produce hydrophilic or inactive
metabolites
 Form more polar and water soluble products
 Enzymes attach small, polar and ionizable
molecules (glucuronic acid, sulfate, glycine and
glutamine) to the Phase I metabolites or to
parent xenobiotics.
 Conjugating group includes glucuronic acid,
sulfate, methyl and acetyl groups
 Regarded as a truly detoxifying pathway in drug
metabolism
GLUCURONIC ACID CONJUGATION
 Glucuronidation is the most common conjugative
pathway in drug metabolism for the following
reasons:
Readily available supply of d-glucuronic acid (from
glucose)
Numerous functional groups that combine enzymatically
with glucuronic acid
Glucuronyl moiety, polar hydoxyl groups which greatly
increases water solubility when attached to the
xenobiotics substrate.
 Combine with chemically reactive compound to
form to prevent damage to important
biomolecules
GLUCURONIC ACID
Formation of ß-glucuronides involves two
steps:
synthesis of an coactivated enzyme (uridine5’diphopho, ∂-D glucoronic acid (UDPGA)
Transfer of the glucuronyl group from UDPGA
to an appropriate substrate.
FUNCTIONAL GROUPS THAT UNDERGO GLUCURONIDATION
A. OXYGEN GLUCURONIDES
a.1 Hydroxyl Compounds
- Phenols: morphine, acetaminophen, phydroxyphenytoin
- Alcohols: trichloroethanol, chloramphenicol,
propranolol
- Enols: 4-hydroxycoumarin
- N-Hydroxyamides: N-hydroxydapsone, Nhydroxy-2-acetylaminoflourene
FUNCTIONAL GROUPS THAT UNDERGO GLUCURONIDATION
a.2 Carbonyl Compounds
- Aryl acids: benzoic acids, salicylic acid
- Arylalkyl acids: Naproxen, Fenoprofen
B. NITROGEN GLUCURONIDES
- Arylamines: 7-amino-5-nitroindazole
- Arylamines: desipramine
- Amides: meprobamate
- Sulfonamides: Sulfisoxazole
- Tertiary Amines: Cyproheptadine,
tripelennamine
FUNCTIONAL GROUPS THAT UNDERGO GLUCURONIDATION
C. SULFUR GLUCURONIDES
- Sulfhydryl groups: methimazole,
propylthiouracil, diethylthiocarbamic
acid
D. CARBON GLUCURONIDES
-3,5Pyrazolidinedione:
phenylbutazone, sulfinpyrazone
GLUCURONIDATION PROCESS SHOWING THE SITE
OF GLUCURONIDES ATTACHMENT TO THE
METABOLITE
MORPHINE(INSERT STRUCTURE)
ACETAMINOPHEN
PROPRANOLOL
CHLORAMPHENICOL
SULFATE CONJUGATION
Process occurs primarily with phenols,
alcohols, aromatic amines, and N-hydoxy
compounds.
The body uses portion of sulfate pool to
conjugate emdogenous compounds such
as steroids, heparin, chondroitin,
catecholamine, and thyroxine.
Involves the activation of inorganic sulfate
to its co-enzyme.
SULFATE CONJUGATION
Phenols are main groups of substrates
that undergo conjugation.
Drug containing phenolic moiety are often
susceptible to sulfate formation.
Conjugation with glycine, glutamine, and
other Amino Cids
Conjugates carboxylic acids particularly
aromatic and arylaklyl acids.
Example: (insert photo)
Benzoin Acid
Salicylic acid
Conjugation with GSH or Mercapturic acid
 Important pathway for detoxifying chemically
reactive electrophilic compounds.
 Called glutamyl-cysteinylglycine (found in most
tissues)
 Process involves enzymatic cleavage of two
amino acid – glutamic acid and glycine)
 Its conjugation is catalyzed by an enzyme known
as glutathione S-transferase.
 Degradation of GSH is due to renal and hepatic
microsomal enzymes
Conjugation with GSH or Mercapturic acid
Example:
insert structure of brompheniramine
Haloperidol, Diphenhydramine
ACETYLATION
Constitutes a metabolic route for drugs
containing primary amino groups, which
includes the following:
Aromatic amines (ArNH2)
Sulfonamides (H2NC6H4SO2NHR)
Hydrazines (NHNH2 )
Hydrazides (-CONHNH2)
Aliphatic amines
ACETYLATION
Derivatives formed from these amino
functionalities are inactive and non-toxic.
Its primary function is the termination of
pharmacological activity and detoxification
Less water solubility
Acetyl group used is acetyl-CoA
METHYLATION
Inactivation of physiologically active
biogenic amines
Does not convert metabolites to become
more water soluble except when it creates
a quaternary ammonium derivative.
Most of the products end up
pharmacologically inactive
METHYLATION
Foreign compounds that undergo
methylation includes:
Cathecols,phenols, amines and N- heterocyclic
and thiol compounds.
Anihypertensive drugs (methyldopa)
Antiparkinsonism agent (levodopa)
Norephenephrine and Dopamine
FACTORS THAT AFFECTS DRUG
METABOLISM