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Metabolic Changes of Drugs
Books: 1. Wilson and Gisvold’s Textbook of Organic Medicinal and
Pharmaceutical Chemistry 11th ed. Lippincott, Williams & Wilkins ed.
2. Foye’s Principles of Medicinal Chemistry
3- Burger's Medicinal Chemistry &Drug Discovery.
Prof. Faris T. Abachi ( PHD Pharmacy)
3rd Year Pharmacy
2017
outlines
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Introduction
Definitions.
General pathways of drug
metabolism
Sites of drug biotransformation
Role of Cytochrome P-450 Enzymes
Classification.
Introduction
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Metabolism play a central role in the
elimination of drugs and other
foreign compounds ( Xenobiotics)
from the body.
A solid understanding of drug
metabolism pathways is an essential
tool for pharmacists in their role of
selecting and monitoring appropriate
drug therapy for their patients.
Definitions
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Biochemically speaking: Metabolism means Catabolism
(breaking down of substances) + Anabolism (building up or
synthesis of substances)
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But when we speak about drug metabolism, it is only catabolism
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That is drug metabolism is the break down of drug molecules
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So what is building the drug molecules? We use the word
“synthesis”, then
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Biotransformation: It is a specific term used for chemical
transformation of xenobiotics in the body/living organism.• a
series of enzyme-catalyzed processes—that alters the
physiochemical properties offoreign chemicals (drug/xenobiotics)
from those that favor absorption across biologicalmembranes
(lipophilicity) to those favoring elimination in urine or bile
(hydrophilicity )
What Roles are Played by Drug Metabolism?
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Xenobiotics : These are all chemical substances that are not nutrient for
body (foreign to body) and which enter the body through ingestion,
inhalation or dermal exposure. They include : drugs, industrial
chemicals, pesticides, pollutants, plant and animal toxins, etc.animal
toxins,
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One of four pharmacokinetic parameters, i.e., absorption, distribution,
metabolism and excretion (ADME)
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Elimination of Drugs: Metabolism and excretion together are elimination
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Xenobiotics : These are all chemical substances that are not nutrient for
body (foreign to body) and which enter the body through ingestion,
inhalation or dermal exposure. They include : drugs, industrial
chemicals, pesticides, pollutants, plant and animal toxins, etc
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Many drugs are metabolically activated (Prodrugs)
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Sometimes drugs become more toxic and carcinogenic
Sites/Organs of drug metabolism
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The major site of drug metabolism is the
liver (microsomal enzyme systems of
hepatocytes)Secondary organs of
biotransformation• kidney (proximal
tubule)• lungs (type II cells)• testes (Sertoli
cells)• skin (epithelial cells); plasma.
nervous tissue (brain); intestines
Enzymes are divided into TWO types:
1-Microsomal enzymes:
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The endoplasmic reticulum (especially
smooth endoplasmic reticulum) of liver
and other tissues contain a large variety of
enzymes, together called microsomal
enzymes (microsomes are minute
spherical vesicles derived from
endoplasmic reticulum after disruption of
cells by centrifugation, enzymes present in
microsomes are called microsomal
enzymes).
2- Non-microsomal enzymes:
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Enzymes occurring in organelles/sites other than
endoplasmic reticulum (microsomes) are called
non-microsomal enzymes. These are usually
present in the cytoplasm, mitochondria, etc. and
occur mainly in the liver, Gl tract, plasma and
other tissues. They are usually non-specific
enzymes that catalyse few oxidative reactions, a
number of reductive and hydrolytic reactions,
and all conjugative reactions other than
glucuronidation
General pathways of drug
metabolism
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Drug metabolism reactions have
been divided into TWO categories
PHASE I ; Functionalization
PHASE II ; Conjugation
Phase l
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Oxidation reactions
Aromatic, olefins, benzylic, alicyclic,
c-c hetero atoms , N – oxidation, S
oxidation, ..
Reduction reactions
Aldehydes, ketones, nitro, azo ,..
Hydrolytic reactions
Hydrloysis of esters & amides
Phase II
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Glucuronic acid conjugation
Sulfate conjugation
Glycine, glutamine A.A conjugation
Glutathione or mercapturic acid
conjugation
Acetylation
Methylation
Compare between phase I &ll
Phase l
Phase
ll
large
Small
Non-polar ( lipophilic )
Polar
Metabolite to another product
active
Excretion to the urine
Not active
Metabolite Examples and notes
activity
Routes that result in the formation of inactive metabolites are often referred to as detoxification.
Inactive
OH
O
O
(detoxification)
Phenol sulphokinase
S
O
3'-Phosphoadenosine-5'phosphosulfate (PAPS)
Phenol
Similar activity
to the drug
OH
Phenyl hydrogen sulfate
The metabolite may exhibit either a different potency or duration of action or both to the
original drug.
CH3
CH3
O
O
O
N
Hydroxylation
N
Cl
H
N
N
OH
N-Demethylation
Ph
Diazepam
(Sustained anxiolytic action)
N
Cl
N
Cl
OH
Ph
Oxazepam
(short duration)
Ph
Temazepam
(Short duration)
CH3
CONHNHCH
CONHNH2
CH3
Different
activity
N-Dealkylation
N
Ipronazid
(Antidepressant)
N
Isoniazid
(Antituberculosis)
HO
Toxic
metabolites
NCOCH3
NHCOCH3
NH2
Other substances
responsible for
hepatotoxicity
Substances responsible
for methemoglobinamia
OC2H5
N-Hydroxyphenacetin
(Hepatotoxic)
OC2H5
Phenacetin
(Analgesic)
OC2H5
Phenetidine
Sites of Drug Metabolism
 Liver: Major site, well organized with all enzyme systems
The first-pass effect
Following drugs are metabolized extensively by first-pass effect: Isoproterenol,
Lidocaine Meperidine, Morphine, Pentazocine, Propoxyphene, Propranolol,
Nitroglycerin, Salicylamide
 Intestinal Mucosa: The extra-hepatic metabolism, contains CYP3A4 isozyme
 Isoproterenol exhibit considerable sulphate conjugation in GI tract
 Levodopa, chlorpromazine and diethylstilbestrol are also reportedly metabolized
in GI tract
 Esterases and lipases present in the intestine may be particularly important
carrying out hydrolysis of many ester prodrugs
 Bacterial flora present in the intestine and colon reduce many azo and nitro
drugs (e.g., sulfasalazine)
 Intestinal b-glucuronidase can hydrolyze glucuronide conjugates excreted in the
bile, thereby liberating the free drug or its metabolite for possible reabsorption
(enterohepatic circulation or recycling)
Enzymes Involved in Drug Metabolism
CYP450, Hepatic microsomal flavin containing monooxygenases (MFMO
or FMO) Monoamine Oxidase (MAO) and Hydrolases
 Cytochrome P450 system: localized in the
smooth endoplasmic reticulum.
 Cytochrome P450 is a Pigment that, with CO
bound to the reduced form, absorbs maximally at
450nm
 Cytochromes are hemoproteins (heme-thiolate)
that function to pass electrons by reversibly
changing the oxidation state of the Fe in heme
between the 2+ and 3+ state and serves as an
electron acceptor–donor
 P450 is not a singular hemoprotein but rather a
family of related hemoproteins. Over 1000 have
been identified in nature with ~50 functionally
active in humans with broad substrate specificity
Simplified apoprotein portion
HOOC
CH3
L
N
N
Fe+3
N
N
CH3
CH2
CH3
HOOC
CH3
CH2
O
H R
Substrate binding site
Heme portion with
activated Oxygen
Cytochrome P450: Naming
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Before we had a thorough understanding of this enzyme system, the
CYP450 enzymes were named based on their catalytic activity toward a
specific substrate, e.g., aminopyrine N-demethylase now known as
CYP2E1
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Currently, all P450’s are named by starting with “CYP” (CYtochrome P450,
N1, L, N2 - the first number( Arabic number ) is the family (>40%
homology), the letter is the subfamily (> 55% homology), and the second
number is the isoform. The majority of drug metabolism is by ~10 isoforms
of the CYP1, CYP2 and CYP3 families in humans
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Major human forms of P450: Quantitatively, in the liver the percentages of
total P450 protein are: CYP3A4 – 28%, CYP2Cx – 20%, CYP1A2 – 12%,
CYP2E1 – 6%, CYP2A6 – 4%, CYP2D6 – 4%
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By number of drugs metabolized the percentages are: CYP3A4 – 35%,
CYP2D6 – 20%, CYP2C8 and CYP2C9 – 17%, CYP2C18 and CYP2C19
- 8% CYP 1A1 and CYP1A2 -10%, CYP2E1 – 4%, CYP2B6 – 3%
Drug Interactions & Metabolism
The drug interactions depend upon:
a) the isoform(s) required by the drug in question,
b) the isoforms altered by concomitant therapy,
c) the type of enzyme alteration (induction or
inhibition).
General Metabolic Pathways
Hydrolytic Reactions
 Esters and amides
 Epoxides and arene oxides
by epoxide hydrase
Phase II Conjugation
Phase I Functionalization
Drug
Metabolism
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Glucuronic acid conjugation
Sulfate Conjugation
Glycine and other AA
Glutathion or mercapturic acid
Acetylation
Methylation
Oxidation
 Aromatic moieties
 Olefins
 Benzylic & allylic C atoms
and a-C of C=O and C=N
 At aliphatic and alicyclic C
 C-Heteroatom system
C-N (N-dealkylation, N-oxide
formation, N-hydroxylation)
C-O (O-dealkylation)
C-S (S-dealkylation, S-oxidation,
desulfuration)
 Oxidation of alcohols and
aldehydes
 Miscellaneous
Reduction
 Aldehydes and ketones
 Nitro and azo
 Miscellaneous
Tetrahydrocannabinol (D1-THC) Metabolism
7
CH3
6
5
1
4
2
CH2OH
OH
OH
3
H3C
O
CH3
D1-THC
COOH
C5H11
OH
H3C
H3C
O
CH3
C5H11
O
CH3
7-Hydroxy-D1-THC
C5H11
D1-THC-7-oic Acid
COOR
OR
COOO
Where R =
H3C
O
CH3
C5H11
Glucuronide conjugate at either
COOH or phenolic OH group
H
OH
OH
HO
b-Glucuronyl
moiety
The metabolite is polar, ionisable and hydrophilic
Oxidative Reactions
Arenols
OH
Arene Oxides
O
Epoxides
O
C C
C
C
Benzylic, allylic
aliphatic C
Hydroxylation
C OH
C H
R N H
"Activated Oxigen"
Miscellaneous
Oxidations
[FeO]
S C
S P
O C
O P
Desulfuration
R N OH
R N CH2R
3+
R O CH3
R N
R NH + O CHR
R N
O
S CH3
R OH
O
O-Dealkylation
SH,
S CH3
S-Dealkylation
and S-Oxidation
N-Hydroxylation
N-Dealkyaltion and
Oxidative Deamination
N-Oxide Formation
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Hydroxylation is the primary reaction mediated by CYP450
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Hydroxylation can be followed by non-CYP450 reactions including
conjugation or oxidation to ketones or aldehydes, with aldehydes
getting further oxidized to acids
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Hydroxylation of the carbon α to heteroatoms often lead to cleavage of
the carbon – heteroatom bond; seen especially with N, O and S,
results in N–, S– or O–dealkylation.
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Must have an available hydrogen on atom that gets hydroxylated, this
is important!!!
Aromatic Hydroxylation
R1
R1
R1
Spontaneous
CYP450
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O
Mixed function oxidation of arenes to
arenols via an epoxide intermediate
arene oxide
Occurs primarily at para position
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Substituents attached to aromatic ring
influence the hydroxylation
R1
R1
Epoxide
hydrolase
Epoxide
Hydrase
Major route of metabolism for drugs with
phenyl ring
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OH
Aromatase
OH
OH
R1
Glutathione
OH
S
Activated rings (with electron-rich
substituents) are more susceptible while
deactivated (with electron withdrawing
groups, e.g., Cl, N+R3, COOH,
SO2NHR) are generally slow or
resistant to hydroxylation
OH
OH
Glutathione
R1
Macromolecule
OH
Macromolecule
HOME WORK
Oxidation of Benzene Ring.
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1- Phenytoin
2-Warfarin
3-Propanolol
4-phenybutazone
5- Steroid ( 17-α- Ethyinyestradiol)
6- Atrovastain
H
H
H
CYP2C19
N
HO
O
N
O
O
N
H
Phenytoin
H
CH3
O
O
H
N
N
Amphetamine
p-hydroxyphenytoin
O
OH
OH
O
C CH
H
N
CH3
ONa
CH3
O
HO
Warfarin sodium
17-a-Ethinylestradiol
O
HO
C
Propranolol
Ca+2
O
OH
O
CH3
HN
N
F
N
H3C
CH3
CH3
N
O
C
O
Phenylbutazone
2
Atorvastatin