Transcript Drug Metabolism in the Human Body: Tylenol

By: Sundeep Master
Essentially, drug metabolism is a process that converts drugs, after
absorption, to products that can be easily excreted from the body. This is a 2
two phase system; the first phase consists of biotransformation reactions
which convert drugs to polar metabolites, and the second phase which takes
some of these metabolites and converts them to molecules which can be
excreted more easily. Phase 2 only occurs in the presence of certain
functional groups, and the different reactions that occur are dictated by the
functional group contained in the molecule. All of these ideas will be
illustrated through the metabolism of aniline, which is the precursor to
acetaminophen. The aniline molecule undergoes a phase 2 acylation, and
then a phase I aromatic hydroxylation. This product is then acetaminophen,
which then undergoes various phase 2 reactions through the Glutathione
conjugation pathway to produce glucoronidated molecules that are easily
excreted.
Outline
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What is Drug Metabolism
Principle Reaction Sequence
Phase I of Drug Metabolism
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Overview of biotransformation reactions
Examples of organic chemical processes
Phase II of Drug Metabolism
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Conjugation Pathways
Glucoronidation reactions and examples
What Happens When You Take Tylenol
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Explanation of the reactions of aniline, the precursor to
Tylenol
Explanation of this pathway graphically.
What is Drug Metabolism
• Results include decreased ability to cross
membranes due to increased polarity and
conversion into readily excreted products
• Also works toward detoxification; a decrease in
the pharmacological activity
• Occurs primarily in Liver, but also in
gastrointestinal tract, lung, kidney and skin
• Xenobiotic- an unexpected chemical substance in
the body
• Lipophillic- capable of dissolving in lipids
(hydrophobic)
Principle Reaction Sequence
Xenobiotic
Elimination
Metabolite(s)
Inactive
Metabolite(s)
Reactive
Intermediate
Covalent
Binding
Tissue
Injury
Inadvertent
Reaction
Sequence
Cancer
Death
Murray
Anderson
Phase I
• Phase 1 reactions use enzymes to convert
substance to polar body (metabolite). Known as
biotransformation reaction
• Functional groups are added to molecule for
further Phase II conjugation
• Phase I reactions also make lipophillic
molecules more polar
• Major Phase I reactions include hydroxylations,
oxidations, reductions and hydrolysis
Phase I
• Major oxidation scheme is known as
Cytochrome P450 (CYP450) system
• Function of this system includes manufacturing
steroids, unsaturated fatty acids and bile acids,
which aid in detoxification
• Molecule undergoes different reactions based on
initial functional group due:
– Aromatic compounds = hydroxylation
– Alcohols = oxidized to carboxylic acid via aldehyde
– Nitrogen, Sulfur and Oxygen compounds with alkyl
groups = dealkylation
– Esters and Amides = reduction
Examples of CYP450 Reactions
Sulfoxidation
O
S
Cl
S
N
Cl
CH2 CH2 CH2
N
N(CH3 )2
CH2 CH2 CH2
Chlorpromazine
N(CH3 )2
Chlorpromazine Sulfoxide
Hydrolysis
COOH
H2O
COOH
+
O C CH3
CH3COOH
OH
O
Reduction
O
H3C C
O
NADPH (H+)
OH
H3C CH
SO2NH C NH
Murray
O
SO2NH C NH
Phase II
• Phase II reactions are known as
conjugation reactions.
• Polar functional groups are attached to
polar molecules produced by phase I
reactions
• Greater polarity enables excretion by urine
of feces.
• Major pathways include glucuronidations
and glutathione conugation
Glucuronidation Pathway
• Pathway occurs via
Glucuronic Acid
intermediate
• Major conjugation
reaction due to
ready supply of
glucose
• Occurs frequently
with hydroxy and
carboxy groups
CH2OH
PPi
UTP
O
OH
CH2OH
2 NAD+
O
COO2 NADH(H+)
OH
O-PO3 2-
OH
OH
OH
O
OH
O-UDP
OH
UDP-Glucose
Glucose-1-P
O-UDP
OH
OH
UDP-Glucuronic Acid
COOO
OH
O
OH
OH
OH
O
O
Testosterone
Murray
Phenols and Sulfate Conjugation
• Phenol compounds undergo sulfate
(SO42-) conjugation
• Not as prevalent as glucuronidation due to
lower levels of sulfate
InChem
Acetylations
• Compounds with primary aromatic amines,
hydrazides and hydrazines
• Differs because less polar derivatives are
created, but it reduces pharmacological effect
H2N
SO2NH2
CH3-C-NH
SO2NH2
O
N4-Acetylsulfanilamide
Murray
Glutathione Conjugation
Pathway
• Another reaction pathway serves as last step for
elimination of drug
• Pathway leads to the formation of mercapturic
acid derivative which is easily excreted in urine
University of Michigan
Summary
• Drug metabolism is an important topic due to its impact
on our daily lives. Essentially, a lipophillic compound
which is absorbed goes through a Phase I pathway and
becomes more polar. This compound may then be
excreted, or may have to go through the conjugation
(Phase II) pathway. The end result is a hydrophillic,
polar compound that is easily excreted in the urine or
feces, or a decreased pharmacological effect of the
compound. Drug metabolism is necessary as some of
the side products produced, as well as some of the
compounds themselves, can be toxic if not excreted from
the body, or at the very least, not detoxified properly.
Additionally, studying these pathways provides
information that is important and extremely helpful in the
Pharmaceutical world, as drug discovery relies heavily
on the reactions each compound undergoes in the body
NH2
NH
NH2
Hb-Fe2+
Hb-Fe3+
Phase I
Methemoglobinemia
Aromatic
Hydroxylation
Aniline
OH
O
Phase II
Phase II
Acetylation
Sulfate + Glucuronide
NHCOCH3
NHCOCH3
Phase I
NHCOCH3
Phase II
Aromatic
Hydroxylation
OH
Acetaminophen
Phase
II
O-Glucuronide
NHCOCH3
O
COCH3
+
NH
N
OH
OSO3-
(Sulfate)
O
Reactive Intermediates
Nucleophilic Cell
Macromolecules
Glutathione
NHCOCH3
NHCOCH3
Nucleophile
S-Glutathione
OH
OH
CELL DEATH
Mercapturic Acid
Derivative
Murray
References
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B. Katzung, Basic and Clinical Pharmacology, 8th Edition, Lange/McGraw-Hill, 2001,
Chapter 4, p. 51 – 63.
Murray, Wallace. “Xenobiotic Metabolism and Metabolism Enzymes.” Western
University Notes. 2003
Levy, G. “Sulfate conjugation in drug metabolism: role of inorganic sulfate.” Fed
Proc. Journal. July 1986. 2235-40
http://wwwpersonal.une.edu.au/~sglover/CHEM303%20Chapter%202%20HTML/sld075.htm
InChem: http://www.inchem.org/documents/ehc/ehc/ehc006.htm
https://www.sigmaaldrich.com/Area_of_Interest/Biochemicals/Enzyme_Explorer/Key_
Resources/Metabolic_Pathways.html
http://home.ccr.cancer.gov/metabolism/friedman/fkfccr.htm
http://www.ionsource.com/tutorial/metabolism/met_slide2.htm
Wikipedia: The Free Encyclopedia (17 March 2006).
http://en.wikipedia.org/wiki/Main_Page 16 March 2006
Anderson, Peter. “The ABCs of Pharmacokinetics”.
http://www.thebody.com/tpan/winter05/abcs.html