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Metabolic Changes of Drugs and Related Organic Compounds

This chapter discusses drug metabolism and biotransformation. It describes the various phases of drug metabolism, including phase I reactions like oxidation, reduction, and hydrolysis that make the drug more polar. Phase II or conjugation reactions then combine these metabolites with endogenous compounds like glucuronic acid, glutathione, sulfate, or acetyl groups via transferase enzymes to further increase polarity and allow excretion. The key conjugation reactions are glucuronidation, acetylation, glutathione conjugation, sulfation, and methylation. Understanding how drugs are metabolized helps explain interactions between drugs and individual variability in drug responses.

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Micah Lou Calamba
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51 views20 pages

Metabolic Changes of Drugs and Related Organic Compounds

This chapter discusses drug metabolism and biotransformation. It describes the various phases of drug metabolism, including phase I reactions like oxidation, reduction, and hydrolysis that make the drug more polar. Phase II or conjugation reactions then combine these metabolites with endogenous compounds like glucuronic acid, glutathione, sulfate, or acetyl groups via transferase enzymes to further increase polarity and allow excretion. The key conjugation reactions are glucuronidation, acetylation, glutathione conjugation, sulfation, and methylation. Understanding how drugs are metabolized helps explain interactions between drugs and individual variability in drug responses.

Uploaded by

Micah Lou Calamba
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Chapter 3

METABOLIC CHANGES OF DRUGS AND


RELATED ORGANIC COMPOUNDS

OBJECTIVES
 To identify the site of biotransformation of drug
 To describe various phases of drug metabolism
 To understand why certain drugs are contradicted with other drugs
 To become aware of the metabolism currently used therapeutic
agents
Drug Metabolism

 The biochemical changes that occur on drugs or other foreign


compounds, the purpose of which is to facilitate elimination.
 Without it, xenobiotics can remain indefinitely in the body.
 It may lead to the formation of inactive and non toxic
compounds, hence the term detoxification .
 However, more recent studies have shown that some
metabolites are not only active but toxic.
PRODUCT OF METABOLISM

PRORUGS/MET XENOBIOTICS
Must be
ABOLITES
converted to
Are mostly
a water
lipophilic or
soluble
lipid soluble substance(hyd
compounds rophilic)
Phase II or Conjugation reaction
 Phase II or conjugation (latin, conjugatus = yoked together)
reactions involve combination of a drug or its PHASE I metabolite
with an endogenous substance to form a highly polar product,
w/c can be efficiently excreted in the body.
 Uses enzymes (transferases) to attach small endogenous polar
molecules to a drug.
 these endogenous compounds are:
*GLUCORONIDATION
*ACETYLATION
*GLUTATHIONE
* SULFATION
*METHYLATION
Phase II or Conjugation reaction
* Involves the following conjugation reactions that are catalyzed by transferase
enzymes: GLUCORONIDATION, ACETYLATION, GLUTATHIONE, SULFATION and
METHYLATION
Type of Endogenous Transferase Types of substrates Examples
conjugation reactant (enzymes)
UDP glucuronic UDP Phenol and Morphine,
acid (UDPGA) glucuronyltransfer alcohol, acetaminophen,
Glucuronidati a- carboxylic acids, diazepam,
on se hydroxylamides, digitoxin, digoxin
sulfonamides

Acetylation Acetyl-Coa N-
Acetyltransferase
Amines Sulphonamides,
isoniazid,
clonezepam,
dapsone,
mescaline

Glutathione Glutathione GSH-S-transferase Epoxides, arene


oxides, nitro
Acetaminophen,
bromobenzene
(GSH)
groups,
Hydroxylamines

Sulfation Phosphoadenosyl
phosphosulfate
Sulfotransferase Phenols, alcohols,
Aromatic amines
Aniline, phenol,
acetaminophen,
Glucuronidation (Glucuronic acid
conjugation)
• Readily available of supply of D-glucuronic acid
(derived from d glucose)
• Numerous functional group that can combine
enzymatically with glucuronic acid when attached to
xenobiotic substrates, greatly increases the water
solubility of the conjugated product.
• Phenolic and alcoholic hydroxyls are the most
common functional groups undergoing
glucuronidation in drug metabolism.
 Morphine, acetaminophen and p-hydroxyphenytoin are a few
examples
of phenolic compounds that undergo considerable glucuronidation.

Arrows indicate
sites of B-
glucuronide
 Alcoholic hydroxyls, such as those present in trichloroethanol,
attachment
chloramphenicol and propranolol are conjugated.
Glucuronic acid conjugation or
Glucuronidation
 A drug must have a group capable of forming bond
with the endogenous compound.
Sulfation (sulphate conjugation)

 Occurs primarily for phenols and occasionally for


alcohols, aromatic amines and N-hydroxyl
compounds
 Catalyzed by sulfotransferase enzyme
Glutathione (Mercapturic Acid)

•
• Its conjugation is catalyzed by an enzyme
known as glutathione S-transferase.
•
• Degradation of GSH is due to renal and
hepatic microsomal enzymes
•
ACETYLATION

 Derivatives formed from these amino functionalities are inactive


and non-toxic.
 Less water solubility
 Its primary function is the termination of pharmacological activity
and detoxification
 Acetyl group used is acetyl-CoA
METHYLATION

 Most of the products end up


pharmacologically inactive
 Adding methyl groups to endogenous
compound
 Catalyzed by enzyme transmethylases
METHYLATION

Foreign compounds that undergo methylation


includes:
 Cathecols,phenols,amines and N-
heterocyclic and thiol compounds.
 Antihypertensive drugs (methyldopa)
 Antiparkinsonism agent (levodopa)
 Norephenephrine and Dopamine

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