Transcript Slide 1
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