Post on 14-Apr-2018
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Drug metabolism
Metabolic processes, in general, have the
overall effect of converting drug molecules
into more polar compounds.
The effect of this have been divided into two
major categories:
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Phase 1 Reaction
Human Hepatic Cytochrome Enzyme System CYP
450 s:
Oxidation is probably the most common reaction in
drug metabolism.
This reaction catalyzed by a group of membrane-
bound monooxygenase found in the smooth
endoplasmic reticulum of the liver and other extra
hepatic tissues, called the cytochrome P 450
monooxygenase enzyme system.
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Phase 1 Reaction
Reactions involved in Phase 1:
A) Oxidative reactions
B) Reductive reactions C) Hydrolytic reactions.
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A) Oxidative reactions
1. Methyl substituents on the carbon skeleton of
a drug are often oxidized to form alcohols,
which may be oxidized further to carboxylic
acid.
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A) Oxidative reactions:
2. The oxidation of Alkenes yield primarily
epoxide, and aromatic ring may also.
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A) Oxidative reactions:
3.Aromatic hydroxylation:
For monosubstituented benzene compounds,
para hydroxylation usually predominates.
(Phenytoin)
(Acetanilide metabolite to Paracetamol)
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A) Oxidative reactions
4. Oxidation of alcohols and aldehydes:
Alcohol oxidized to aldehyde if primary, or
ketone if secondary.
Aldehyde metabolites often undergo oxidation
to generate carboxylic acid derivatives.
(Medazepam to 2-hydroxymedazepam toDiazepam)
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A) Oxidative reactions
5. O- and S-Dealkylation:
O-Dealkylation (Codeine to Morphine).
S-Dealkylation (6-Methylmercaptopurine to 6-Mercaptopurine).
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O-Dealkylation:
O-Dealkylation (Codeine to Morphine)
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S-Dealkylation (6-Methylmercaptopurine to 6-
Mercaptopurine).
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A) Oxidative reactions
6. N-Dealkylation:
The dealkylation of secondary and tertiary
amines to yield primary and secondary amine.
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N-Dealkylation:
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N-Dealkylation:
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A) Oxidative reactions
7.Oxidative Deamination :
Oxidative deamination can occur with alpha
substituted amine, by Amphetamine.
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Oxidative Deamination :
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A) Oxidative reactions
8.Dehalogenation: (Halothane)
An excellent example of oxidative dehalogenation
leading to significant hepatotoxicity and
nephrotoxicity is seen with the fluorinated
inhahation anesthetics.
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B) Reductive reactions
1. Carbonyl reduction: Ketones often lead to the
creation an alcohol.
(Reduction of Acetophenone)
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B) Reductive reactions
2. Nitro reduction:
Aromatic nitro drugs undergo enzymatic
reduction to the amines.
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3. Azo reduction:
A number of azo compounds, such as prontosil
are converted to primary amines.
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C) Hydrolytic reactions
1. Hydrolysis of ester and amide:
in many drugs catalyzed by hydrolytic
enzymes.
The metabolic products formed, carboxylic
acid, alcohol, and carboxylic acid, amine.
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Phase 11 Reactions (Conjugation)
1. Glucuronic Acid Conjugation:
Glucuronide formation is probably the major
and most common route for drug phase 2
metabolism to water-soluble metabolites.
Account for the major share of the conjugated
metabolites found in the urine and bile.
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Phase 11 Reactions (Conjugation)
The formation of glucuronides involves two
steps:
1. The synthesis of an activated coenzyme
uridine-5-diphospho-D-glucuronic acid
(UDPGA).
2. The transfer of the glucuronyl moiety to the
substrate catalyzed by glucuronyltransferases
with inversion of configuration at C-1.
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Phase 11 Reactions (Conjugation)
2. Sulfate Conjugation:
It is an important reaction in the
biotransformation of steroid hormones,
catecholamine neurotransmitters, thyroxine,
bile acid, phenolic drugs and others.
Inorganic sulfate is first converted to a high-
energy nucleotide, 3-phosphoadenosine-5-
phosphosulfate.
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Phase 11 Reactions (Conjugation)
The sulfate group is then transferred to a
variety of aromatic and aliphatic OH, or NH2 ,
the reaction is mediated by sulfontrasferases
present in the liver and other tissues.
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Phase 11 Reactions (Conjugation)
3. Amino acid Conjugation:
Drugs bearing a carboxylic acid group can
become conjugated to amino acids by the
formation of a peptide link.
The carboxylic acid present in the drug is first
activated by formation of a coenzyme A
thioester which is then linked to the amino
acid.
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Phase 11 Reactions (Conjugation)
4. Glutathione conjugation:
Epoxides, alkyl halides and sulfonate can react
with the thiol group of the glutathione to give
glutathione conjugates which can be
subsequently transformed to mercapturic acid.
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Phase 11 Reactions (Conjugation)
5. Acetylation Conjugation:
It is principally a reaction of amino groups
involving the transfer of acetyl-CoA to
primary aliphatic and aromatic amines, amino
acid , hydrazine, or sulfonamide groups.
The liver is the primary site of acetylation.
Secondary amines are not acetylated.
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Phase 11 Reactions (Conjugation)
6. Methylation:
Methylation differs from other conjugation
processes in that the O-methyl metabolites
formed may in some cases have as great or
greater pharmacologic activity and
lipophilicity than the parent molecule e.g. the
conversion of norepinephrine to epinephrine.
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The functional groups that are susceptible
to methylation are phenols, amines, and
thiols
Methylation results principally in the
formation of O-methylated, N-methylated
and S-methylated products.
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The most important enzyme for
O-methylations is catechol O-methyltransferase,
which preferentially methylates the meta
position of catechols.
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Problem 1:
You are hired as a consultant to a pharmaceutical companyinterested in developing a new 5-HT selective serotonin-reuptake inhibitor (SSRI), as a new family of antidepressant
drugs. Noting that fluoxetine (Prozac) is in current use, as aSSRI, how you may alter the structure of fluoxetine to prolongits half-life. You could, for example, suggest a very minorchange in the structure of fluoxetine that would retard itsmetabolism, whether by Phase I or Phase II reactions. Please
draw structures and explain your answers.
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