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DRUG METABOLISM
Introductory Concepts
■
Biochemically speaking: Metabolism means Catabolism
(breaking down of substances) + Anabolism (building up or
synthesis of substances)
■
But when we speak about drug metabolism, it is only catabolism
i.e drug metabolism is the break down of drug molecules
■
Metabolism plays a central role in elimination of drugs and other
foreign compounds from the body.
■
Lipid soluble drugs are not excreted satisfactorily in the urine, so
the process of metabolism makes them polar, ionizable and
easily excretable which involve both phase I and phase II
mechanisms.
What Roles are Played by Drug Metabolism?
■
One of four pharmacokinetic parameters, i.e., absorption, distribution,
metabolism and excretion (ADME)
■
Elimination of Drugs: Metabolism and excretion together are elimination
■
Excretion physically removes drugs from the body
The major excretory organ is the kidney. The kidney is very good at excreting
polar and ionized drugs without any major metabolism. The kidney is unable to
excrete drugs with high lipid solubility
■
In general, by metabolism drugs become more polar, ionizable and thus
more water soluble to enhance elimination
■
It also effect deactivation and thus detoxification.
■
Many drugs are metabolically activated (Prodrugs).
■
Sometimes drugs become more toxic and carcinogenic.
Classification of metabolites:
•
•
•
•
Inactive metabolites
Metabolites retain similar activity
Metabolites with different activity
Bioactivated metabolites (prodrug technique)
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
Classification of drug metabolic
pathways
Drug metabolism reactions have been divided into two
classes:
1.
Phase I reaction (functionalization)
2.
Phase II reaction (conjugation)
Phase I reaction (functionalization)
 Purpose of these reactions is to introduce a polar
functional group like –OH, -COOH, -SH, NH2by:
1. Direct introduction of the functional group eg.
Aromatic & aliphatic hydroxylation.
2. Modifying or unmasking existing fuctional groups
eg. Reduction of ketones and aldehydes to
alcohol, oxidation of alcohols to acids, hydrolysis
of esters and amides.
Classification of Phase –I reactions
3. Hydrolytic Reactions
 Esters and amides
 Epoxides and arene oxides
by epoxide hydrase
Phase II Conjugation
Phase I Functionalization
Drug
Metabolism
1. 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
2. Reduction
 Aldehydes and ketones
 Nitro and azo
 Miscellaneous
Phase II reaction (Conjugation)
 Purpose of these reactions is to attached a polar
and ionizable endogenous compounds such as
glucoronic acid, sulfate, glycine and other amino
acids to the functional handles of phase I
metabolites or parent compound.
 These conjugated metabolites are readily excreted
in the urine and are generally devoid of
pharmacological activity.
Classification of Phase II reaction (Conjugation)
Phase I Functionalization
Phase II Conjugation
Drug
Metabolism
1.
2.
3.
4.
Glucuronic acid conjugation
Sulfate Conjugation
Glycine and other AA
Glutathion or mercapturic
acid
5. Acetylation
6. Methylation
General Metabolic Pathways
Hydrolytic Reactions
 Esters and amides
 Epoxides and arene oxides
by epoxide hydrase
Phase II Conjugation
Phase I Functionalization
Drug
Metabolism






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
Sites of Drug Metabolism
 Liver: Major site, well organized with all enzyme systems
 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
1. CYP450 :- Carry out oxidation reactions
2. Hepatic Microsomal Flavin Containing
Monooxygenases (MFMO or FMO):-Oxidize
S and N functional groups
3. Monoamine Oxidase (MAO): carry out NonMicrosomal Oxidation Reactions
4. Hydrolases:- Oxidize S and N functional
groups
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.
Simplified apoprotein portion
 Cytochrome P450 is a Pigment that, with CO
bound to the reduced form, absorbs maximally at
450nm
HOOC
 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
HOOC
 It catalyzes various Oxidation reactions by
activating molecular oxygen and causese
oxidation of diverse substrates(Drugs) by variety
of oxiation reactions.
CH3
N
L
CH3
N
+3
N
CH2
Fe
N
CH3
CH3
CH2
O
H R
Substrate binding site
Heme portion with
activated Oxygen
Oxidative Reactions catalysed by
CYP450.
oxidation Reactions:-
Various types of oxidation reactions:Oxidation
 Aromatic Hydroxylation
 Olefins
 Benzylic & allylic C atoms and a-C of C=O and C=N
 At aliphatic and alicyclic Carbon atom
 C-Heteroatom system
1.C-N (N-dealkylation, N-oxide formation, N-hydroxylation)
2.C-O (O-dealkylation)
3.C-S (S-dealkylation, S-oxidation, desulfuration)
 Oxidation of alcohols and aldehydes
 Miscellaneous
1.AromaticHydroxylation
Hydroxylation
1.Aromatic
■
Hydroxylation is the primary reaction mediated by CYP450
■
Hydroxylation can be followed by non-CYP450 reactions including
conjugation or oxidation to ketones or aldehydes, with aldehydes
getting further oxidized to acids
■
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.
■
Must have an available hydrogen on atom that gets hydroxylated, this
is important!!!
■
Aromatic Hydroxylation
Aromatic Hydroxylation
R1
R1
R1
Spontaneous
CYP450
■
■
O
Mixed function oxidation of arenes to
arenols via an epoxide intermediate
arene oxide
Occurs primarily at para position
■
Substituents attached to aromatic ring
influence the hydroxylation
R1
R1
Epoxide
hydrolase
Epoxide
Hydrase
Major route of metabolism for drugs with
phenyl ring
■
■
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
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
O
H
N
CH3
CH3
CH3
ONa
O
Warfarin sodium
Propranolol
O
HO
C
Ca+2
O
OH
O
CH3
H3C
HN
N
F
N
CH3
N
O
C
O
Phenylbutazone
2
Atorvastatin
O
Cl
H
N
H3C
N
O
N S
OH
O
Cl
HN
H3C
Antihypertensive drug clonidine undergo little
aromatic hydroxylation and the uricosuric
agent probenecid has not been reported to
undergo any aromatic hydroxylation
Probenecid
Clonidine
CH3 O
N
Cl
N
N
N
S
CH3
CH3
Preferentially the more electron rich
ring is hydroxylated
Cl
Diazepam
Chlorpromazine
NIH Shift: Novel Intramolecular Hydride shift named after National Institute of Health where
the process was discovered. This is most important detoxification reaction for arene oxides
R
R
Spontaneous
Rearrangement
NIH Shift
+
O
Arene Oxide
R
R
-
OH
Arenol
H
H
O
H
OH
2.Oxidation of olefinic bonds (also called alkenes)
O
Epoxide hydrolase
Epoxide
Alkene
OHOH
trans dihydrodiol derivative
■
The second step may not occur if the epoxide is stable, usually it is more stable
than arene oxide
■
May be spontaneous and result in alkylation of endogenous molecules
■
Susceptable to enzymatic hydration by epoxide hydrolase to form trans-1,2dihydrodiols (also called 1,2-diols or 1,2-dihydroxy compounds)
HO
O
Epoxide hydrolase
CYP3A4
N
O
N
NH 2
Carbamazepine
(Active)
OH
O
N
NH 2
Carbamazepine 10,11 epoxide
(Active & Toxic)
O
NH2
Carbamazepine trans 10,11 diol
(Inactive)
2.Oxidation of olefinic bonds (also called alkenes)
Protriptyline
Cyproheptadine
3.Benzylic Carbon Hydroxylation
R2
R2
R1
C
R1
H
O
C
O
S
N
H
■
Hydroxylate a carbon attached to a phenol group (aromatic ring)
■
R1 and R2 can produce steric hindrance as they get larger and
more branched
■
So a methyl group is most likely to hydroxylate
■
Primary alcohol metabolites are often oxidized further to
aldehyde and carboxylic acids and secondary alcohols are
converted to ketones by soluble alcohol and aldehyde
dehydrogenase
OH
O
O
N
H
CH3
O
S
CYP2C9
H
H3C
HO
Tolbutamide Metabolism
C
H
O
ONa
N
CH3
O
H3C
Tolmetin sodium
Dicarboxylic acid is the
major metabolite
N
H
O
N
H
CH3
3.Benzylic Carbon Hydroxylation
Imipramine
Amitriptyline
4.Oxidation at Allylic Carbon Atoms
H
The allylic C is the C
atom next to double
bond.
R1
C
C
H
H
C
C
R2 H
H
R3
R1
C
R4
C
R2 H
H
OH
C
C
R3
R4
Eg. Tetrahydrocarnnabinol- it have three allylic centers C3, C6 and C7 but
hydroxylation will take place Preferentially at C7.
7
7CH2OH
CH3
6
5
1
4
2
HO
HO
OH
OH
CH3
CH3
OH
OH
3
+
H3C
H3C
O
CH3
1-THC
C5H11
O
CH3
C5H11
7-Hydroxy-1-THC
+
H3C
O
CH3
C5H11
6a-Hydroxy-1-THC
H3C
O
CH3
C5H11
6b-Hydroxy-1-THC
4.Oxidation at Allylic Carbon Atoms
O-Glucuronide Cojugate
O
O
O
CH3
CH3
O
O
3'
2'
O
O
O
OH
H2C
H2C
3
2
HO
OH
H
HO
N
N
1
H3CO
H3CO
N
Quinine
O
3'-Oxohexabarbital
3'-Hydroxyhexabarbital
Hexabarbital
O
CH3
CH3
CH3
CH3
N
3-Hydroxyquinine
Pentazocine
5.Hydroxylation at a Carbon to C=O and C=N
CH 3
N
R
O
H
C
C
H
R'
R
O
H
C
C
CH 3
O
N
OH N-demethylation
3
N
R' Cl
H
N
O
N
Cl
O
OH
Cl
N
OH
The
benzodiazepines
are classic examples
with both functionalities
(3S) N-Methyloxazepam
or 3-Hydroxydiazepam
Diazepam
(CH3 CH 2 )2 NCH2 CH 2
CH 3
O
N
N
3
N
Cl
Oxazepam
O
3
N
O2 N
F
Flurazepam
The sedative hypnotic
glutethimide possesses
C a to carbonyl function
4
CH2 CH 3
C6 H5
3
Nimetazepam
HO
4
CH2 CH 3
C6 H5
1
O
N
O
H
Glutethemide
O
N
O
H
4-Hydroxyglutethemide
6.Aliphatic Carbon hydroxylation
R1
R1
H
H
H
C
C
C
H
H
H

H
H
H
C
C
C
H
H
H
■
OH
Catalyzes hydroxylation of the ω(terminal
C) and ω-1 carbons in aliphatic chains
Generally need three or more unbranched
carbons .
Alcohol metabolite is formed which further
gives aldehyde, ketone or acid
■
H
R1
H
OH H
C
C
C
H
H
H
H
■
O
H
O
N
O
N
O
CH3
H
O
ω-1
N
OH
O
CH3
O
OH
CYP450
CH3
Ibuprofen Metabolism
H
CH3
O
O
OH
H3C
H 3C
N
CYP450
Pentobarbital Metabolism
H
OH
+
CH3
OH
HOOC
CH3
ω-1
hydroxylation
ω
hydroxylation
6.Alicyclic (nonaromatic ring) Hydroxylation
■
Cyclohexyl group is commonly present in many drug
molecules
■
The mixed function oxydase tend to hydroxylate at the 3 or
4 position of the ring
■
Due to steric factors if position 4 is substituted it is harder to
hydroxylate the molecules
OH
O
O
S
H3C
N
H
O
O
N
H
O
S
CYP450
H3C
O
O
Acetohexamide Metabolism
N
H
O
N
H
7. Oxidation Involving CarbonHeteroatom(C-X) Systems
■ It includes three types of C-X systems:-
A. C-N,
B. C-O
C. C-S (occasionally)
7. Oxidation Involving CarbonHeteroatom(C-X) Systems
■
C-N, C-O and occasionally C-S
■
Two basic types of biotransformation processes:
1.
Hydroxylation of a-C attached directly to the heteroatom (N,O,S).
The resulting intermediate is Hoften unstable and decomposes with
O
H
O
the cleavage
of the C-X bond:
R
X
Ca
R
X
Ca
R
XH
+
Usually Unstable
Oxidative N-, O-, and S-dealkylation as well as oxidative deamination
reaction fall under this category
2.
■
Hydroxylation or oxidation of heteroatom (N, S only, e.g., Nhydroxylation, N-oxide formation, sulfoxide and sulfone formation)
Metabolism of some N containing compounds are complicated by the
fact that C or N hydroxylated products may undergo secondary
reactions to form other, more complex metabolic products (e.g.,
oxime, nitrone, nitroso, imino)
A. C-N systems
■
Aliphatic (1o, 2o, 3o,) and alicyclic (2o and 3o) amines; Aromatic and heterocyclic
nitrogen compounds; Amides
■
Enzyme
H
O
H
■
■
■
3o Aliphatic Rand
N Calicyclic
1
a
amines are metabolized
by
R2
oxidative N-dealkylation
(CYP)
3o or 2o amine
Aliphatic 1o, 2o amines are
susceptible
to
oxidative
H
deamination,
N-dealkylation
Ca
and N-oxidation reactions
NH2
o
Aromatic amines 1undergoes
amine
similar group of reactions as
aliphatic amines, i.e., both Ndealkylation and N-oxidation
R1
N
Ca
O
R1
R2
NH
+
R2
Carbinolamine
2o or 1o amine
H
O
O
Ca
+
NH3
NH2
Carbinolamine
Carbonyl
Ammonia
N-Dealkylation (Deamination)
H
R1
C
N
R3
OH
CYP450
R1
R2 R 4
C
Spontaneous
N
R1
R3
C
R2
R2 R4
O
+
HN
R3
R4
■
Deamination and N-dealkylation differ only in the point of reference; If the drug is R1 or R2
then it is a deamination reaction and If the drug is R3 or R4 then it is an N-dealkylation
■
In general, least sterically hindered carbon (a) will be hydroxylated first, then the next, etc.
Thus the more substituent on this C, the slower it proceeds; branching on the adjacent
carbon slows it down, i.e. R1, R2 = H is fastest.
■
Any group containing an a-H may be removed, e.g., allyl, benzyl. Quaternary carbon
cannot be removed as contain no a-H
■
The more substituents placed on the nitrogen the slower it proceeds (steric hindrance)
■
The larger the substituents are the slower it proceeds (e.g. methyl vs. ethyl). In general,
small alkyl groups like Me, Et and i–Pro are rapidly removed; branching on these
substituents slows it down even more
OH
N
N
CH3
CYP2C19
CH3
Imipramine N-Dealkylation
N
N
CH2
CH3
Spontaneous
N
N
H
CH3
Alicyclic Amines Often Generate Lactams
OH
N
N
N
N
CH3
CH3
N
CH3
N
Cotinine
Carbinolamine
Nicotine
N
N
CH3
CH3
Cyproheptadine
1
C6 H 5
O
3
H 3C
C6 H 5
2
N
H
Phenmetrazine
COOCH 3
HN
Methylphenidate
O
C6 H 5
H 3C
Hydrolysis
N
OH
H
Carbinolamine
intermediate
O
H 3C
N
O
H
3-Oxophenmetrazine
COOH
COOH
HN
HN
Ritalinic Acid
O
O
6-Oxoritalinic Acid
O
Lactum metabolite
CH3
3oAmine drugs
H3C
CH3
N
N
CH3
CH3
H
N
N
C
CH3
O
CH3
H3C
CH3
N
O
O
CH3
Lidocaine
NH2
CH3
Tamoxifen
Disopyramide
CH3
O
N
CH3
CH3
N
N
S
N
CH3
N
CH3
CH3
N
CH3
CH3
Cl
Br
Diphenhydramine
Alicyclic Amine drugs
Chlorpromazine
Benzphetamine
Brompheniramine
CH3
CH3
CH3
N
N
N
H
O
CH3
HO
O
O
Meperidine
Morphine
OH
O
CH3
Dextromethorphan
Metabolism of Tamoxifen
2o & 1o Amines
O
CH3
HN
CH2
CH3
NH3
NH 2
CH3
O
Phenylacetone
Ampetamine
Methampetamine
Cl
NHCH 3
O
Ketamine
CH3
Cl
NH 2
O
Norketamine
Generally, dealkylation of secondary amines occurs before deamination. The rate of
deamination is easily influenced by steric factors both on the a-C and on the N; so it is
easier to deaminate a primary amine but much harder for a tertiary amine.
Exceptions: Some 2o and 3o amines can undergo deamination directly without dealkylation.
OH
O
HN
OH
OH
O
O
O H
Direct Oxidative
CH 3 Deamination
HN
CH 3
H2 N
CH 3
CH 3
Propranolol
OH
OH
O
Oxidative Deamination
Through Primary Amine
O
O
H3C
HN
O
H
CH 3
CH 3
Aldehyde
Metabolite
NH3
Carbinolamine
CH3
NH 2
Primary Amine Metabolite
(Desisopropyl Propranolol)
O
N-Oxidation
H
H
H
OH
N
N
Hydroxylamine
Nitroso
N
O
Aromatic amines
1 aromatic amine
H
H
1° amines
R
C
N
H
R
H
H
C
N
CH3
R
C
H
H
2 amine
H
C
N
H
3 amine
CH3
CH3
R
C
H
H
C
N
N
CH3
N O
CH3
N-Oxide
R
C
H
Nitroso
Nitro
H
R
OH
O
H
CH3
Hydroxylamine
H
R
OH
H
H
3° amines
R
Hydroxylamine
H
2° amines
N
H
1 amine
R
C
H
H
C
N
H
Nitrone
CH2
O
O
N
O
■
The attack is on the unbonded electrons so 3o amines can be oxidized
■
Generally, only occurs if nothing else can happen, so it is a rare reaction
■
Performed by both amine oxidases and hepatic MFO’s
■
Good examples would include amines attached to quaternary carbons since
they cannot be deaminated
H
H3C
N
H
Cl
Chlorphentermine N-Hydroxylation
H
H3C
N
NH2
CH3
Hydroxylamine
Nitroso
H
CH3
Phentermine
N
CYP450
CH3
Cl
H
H3C
Nitro
Amantadine
OH
Amides
B. Oxidation involving C-O System (O-Dealkylation)
H
R1
C
OH
CYP450
O
R3
R1
R2
C
Spontaneous
O
R3
R1
C
R2
O
+
HO
R3
R2
■
Converts an ether to an alcohol plus a ketone or aldehyde
■
Steric hindrance discussion similar to N-dealkylation
OH
O
H3C
H 3C
H3C
O
O
NH2
N
NH2
CY
P4
50
O
O
N
us
eo
tan
on
Sp
H 3C
O
CH2
CH3
OH
N
NH2
N
NH2
H 3C
H 3C
Trimethoprim O-Dealkylation
O
O
N
NH2
N
NH2
CH3
N
H3C
O
H
N
O
O
OH
CH3
CH3
N
O
O
O
OH
O
CH3
Codeine
H3C
H3C
O
O
CH3
Cl
Phenacetin
N
NH2
OH
O
N
N
Indomethacin
N
O
O
H3C
Prazosin
O
Metoprolol
H
N
CH3
CH3
Oxidation involving C-S System
H
■
S-Dealkylation
R1
C
OH
CYP450
S
R3
R1
R2
C
S
R3
Spontaneous
R1
C
R2
R2
Steric hindrance discussion similar to N-dealkylation
O
S
■
Desulfuration
R1
C
R1
R2
C
R2
O
■
R1
S-Oxidation
S
R1
R2
S
O
R2
R1
S
N
N
N
H
6-(Methylthio)-purine
N
S
CH2 OH
N
N
N
N
H
R2
O
Sulfone
Sulfoxide
CH3
S
O
SH
CH2
N
N
N
H
6-Mercaptopurine
N
O
+
HS
R3
O
H3C S
COOH
H
N
O
S CH2C6H5
S
N
O
H
Methitural
CF3
2-Benzylthio-4trifluoromethyl benzoic acid
H3C
H3C
O
S
P
O
O
Parathione
NO2
O
H
H
N
N
O
S
N
O
H
Pentobarbital
N
O
H
Thiopental
H3C
O O
P
O
H3C
O
Paraoxone
NO2
N
O
N
S
S
CH3
S
Ring Sulfoxide
N
CH3
CH3
S
Thioridazine
N
CH3
N
S
N
CH3
S CH3
O
Mesoridazine
N
O S
O
N
CH3
CH3
S
Ring Sulfone
N
N
CH3
S
S
CH3
O O
Sulforidazine
Oxidative Dehalogenation
H
R
C
OH
CYP450
Cl
R
Cl
■
C
O Spontaneous
O
R C
R C
+H2O
Cl
OH
+
+
Cl
Cl
Requires two halogens on carbon
H
■
With three there is no hydrogen available to
replace
■
With one, the reaction generally won’t proceed
■
The intermediate acyl halide is very reactive
OH
OH
O2N
OH
NHCOCHCl2
O2N
Chloramphenicol
O2N
OH
O2N
Cl
OH
HCl
OH
NHCOCCl2
OH
H
Cl
OH
NHCOC OH
O
Oxamic Acid
Derivative
OH
NHCOCCl
O
Oxamyl Chloride
Derivative
Tissue
Nucleophiles
Covalent Binding
(Toxicity)
Hepatic Microsomal Flavin Containing
Monooxygenases (MFMO or FMO)
■
Oxidize S and N functional groups
■
Mechanism is different but end products are similar to those
produced by S and N oxidation by CYP450
■
FMO’s do not work on primary amines
■
FMO’s will not oxidize substrates with more than a single charge
■
FMO’s will not oxidize polyvalent substrates
H3C
S
NH
H
N
N
H
N
N
Cimetidine
C
MFMO
H3C
CH3
S
NH
N
O
N
MFMO
S-Oxidation
H
N
H
N
N
C
CH3
N
Non-Microsomal Oxidation Reactions
■
Monoamine oxidase (outer membrane of mitochondria, flavin containing enzyme )
■
Dehydrogenases (cytoplasm)
■
Purine oxidation (Xanthene oxidase)
Monoamine oxidase
H
R1
C
N
R2 R3
H
R1
C
R2
O
+
H
N
H
R3
■
Two MAOs have been identified: MAO–A and MAO–B. Equal amounts are found in
the liver, but the brain contains primarily MAO–B; MAO–A is found in the adrenergic
nerve endings
■
MAO–A shows preference for serotonin, catecholamines, and other monoamines
with phenolic aromatic rings and MAO–B prefers non–phenolic amines
■
Metabolizes 1° and 2° amines; N must be attached to α-carbon; both C & N must
have at least one replaceable H atom. 2° amines are metabolized by MAO if the
substituent is a methyl group
■
b–Phenylisopropylamines such as amphetamine and ephedrine are not metabolized
by MAOs but are potent inhibitors of MAOs
Alcohol dehydrogenase
R2
R1
C
Aldehyde dehydrogenase
R2
OH
R1
H
C
R1
C
O
O
R1
C
H
O
OH
Metabolizes 1° and 2° alcohols and aldehydes containing at least one “H” attached to a-C; 1°
alcohols typically go to the aldehyde then acid; 2° alcohols are converted to ketone, which
cannot be further converted to the acid. The aldehyde is converted back to an alcohol by
alcohol (keto) reductases (reversible), however, it goes forward as the aldehyde is converted to
carboxylic acid; 3° alcohols and phenolic alcohols cannot be oxidized by this enzyme; No “H”
attached to adjacent carbon
H2
C
Ethanol Metabolism
H3C
Alcohol
Dehydrogenase
OH
H3C
Aldehyde
Dehydrogenase
H
C
OH
H3C
O
C
O
Purine oxidation
O
O
N
HN
N
N
H
Hypoxanthine
Xanthine
oxidase
N
HN
O
N
H
Xanthine
Molybdenum Containing
O
O
N
H
Xanthine
oxidase HN
O
N
H
N
HN
O
OH
N
H
N
H
Uric acid
(hydroxy tautomer)
O
N
H
N
H
Uric acid
(keto tautomer)
Reductive Reactions
■
Bioreduction of C=O (aldehyde and keton) generates alcohol (aldehyde →
1o alcohol; ketone → 2o alcohol)
■
Nitro and azo reductions lead to amino derivatives
■
Reduction of N-oxides to their corresponding 3o amines and reduction of
sulfoxides to sulfides are less frequent
■
Reductive cleavage of disulfide (-S-S-) linkages and reduction of C=C are
minor pathways in drug metabolism
■
Reductive dehalogenation is a minor reaction primarily differ from oxidative
dehalogenation is that the adjacent carbon does not have to have a
replaceable hydrogen and generally removes one halogen from a group of
two or three
Reduction of Aldehydes & Ketones
H
R
C
O
H
Aldehyde
R
C
H
OH
H
1 alcohol
R
C
O
R2
Ketone
R1
C
OH
R2
2 alcohol
■
C=O moiety, esp. the ketone, is frequently encountered in drugs and
additionally, ketones and aldehydes arise from deamination

Ketones tend to be converted to alcohols which can then be glucuronidated.
Aldehydes can also be converted to alcohols, but have the additional
pathway of oxidation to carboxylic acids
■
Reduction of ketones often leads to the creation of an asymmetric center
and thus two stereoisomeric alcohols are possible
■
Reduction of a, b –unsaturated ketones found in steroidal drugs results not
only in the reduction of the ketone but also of the C=C
■
Aldo–keto oxidoreductases carry out bioreductions of aldehydes and
ketones. Alcohol dehydrogenase is a NAD+ dependent oxidoreductase that
oxidizes alcohols but in the presence of NADH or NADPH, the same
enzyme can reduce carbonyl compounds to alcohols.
O
H
O
+
C
R1
O
H
H
HO
H2N
R2
Chiral Alcohol
O
OH H2C
HO
OH H 2C
CH3
H
O
O
CH2
O
CH3
C6H5
H
+
O
O
R,R (+)-Warfarin
O
OH
H3C
O
O
CH3
N
OH
O
OH
H3C
OH
OH H2C
OH
OH
Naloxone
H
O
N
O
Ox Nicotinamide moiety
+
+
of NADP or NAD
H
R,S (+)-Warfarin
R (+)-Warfarin
O
N+
C 6H5
H
HO
+
CH3
C6H 5
O
R2
H2N
R
R
Red Nicotinamide moiety
of NADPH or NADH
Ketone
C
R1
N
H
HO
O
O
O
H2 N
OH
Daunomycin
Naltrexone
CH3
CH3
OH
C
O
OH
H
C
CH
CH
H
HO
Norethindrone
H2
C
CH3
CH
H
H2
C
C
NH2
O
Amphetamine
Phenylacetone
OH
C
OH
H
H
C CH3
NHCH3
(-)-Ephedrine
C
3b,5b-Tetrahydronorethindrone
CH3
H2
C
CH3
CH
OH
1-Phenyl-2-propanol
OH
H
C
CH3
O
1-Hydroxy-1-phenylpropane-2-one
C
H
CH
CH3
OH
1-Phenyl-1,2-propandiol
Reduction of Nitro & Azo Compounds
H
R
C
N
R
O
H
N
C
N
R
O
H
R2
R1
H
H
N
R
H
N
H
N
R
N
N
Azido
NH
H
1 amine
NH2
+
H2N
Two 1 amines
Hydrazo
Azo
R
NH2 + N
Amine
H
N
H
R1
R2
C
OH
Hydroxylamine
Nitroso
N
C
H
Nitro
R1
H
H
O
N2
N
R2

R1 and R2 are almost always aromatic

Usually only seen when the NO2 functional group is attached directly to an
aromatic ring and are rare

Nitro reduction is carried out by NADPH-dependent microsomal and soluble
nitroreductases (hepatic)

NADPH dependent multicomponent hepatic microsomal reductase system
O
O N
reduces the azo
O
2

N
Bacterial reductases in intestine can reduce both nitro and azo
O
H2N
S
NH2
O
N
H2
O
S
H2N
Prontosil
O
H
N
HO
O
Sulfanilamide
N
H2
H2N
+
NH2
NH2
1,2,3-Triaminobenzene
O
S
O
NNa
O
N N
N
H
N
N N
O
O2N
N
OH
N
Cl
Clonazepam
Sulfasalazine
Dantrolene
Reduction of Sulfur Containing Compounds
O
O
Sulfoxide reduction (Cannot reduce a sulfone)
R1
S
R1
R2
S
X
R2
Sulfoxide
R1
S
R2
O
Sulfone
Disulfide reduction
R1
S
S
R2
H3 C
SH
+
N
S
S
N
HS
R2
H3C
CH3
S
H3C
R1
S
H3C
CH3
N
SH
S
N,N-Diethylthiocarbamic
Acid
Disulfiram
O
F
OH
CH3
H
H3 C
S
O
Sulindac
Hydrolytic Reactions
Hydrolyzes (adds water to) esters and amides and their isosteres; the OH from water
ends up on the carboxylic acid (or its isostere) and the H in the hydroxy or amine
■
■
■
Enzymes:
Non-microsomal
hydrolases; however, amide hydrolysis
appears to be mediated by liver
microsomal amidases, esterases, and
deacylases
Electrophilicity of the carbonyl carbon,
Nature of the heteroatom, substituents
on the carbonyl carbon, and
substituents on the heteroatom
influnce the rate of hydrolysis
In
addition,
Nucleophilicity
of
attacking species, Electronic charge,
and Nature of nucleophile and its
steric factors also influence the rate of
hydrolysis
Table: Naming carbonyl - heteroatom groups
R1
R1
R2
Name
Susceptibility
to Hydrolysis
C
O
Ester
Highest

O
C
S
Thioester
C R2
+
O
O
Carbonate
C
N
Amide
O
N
Carbamate
N
N
Ureide
Lowest
The Reactions
O
Ester hydrolysis
R1
O
C
O
R2
R1
C
O
Amide hydrolysis (slower)
R1
C
OH
HO
R2
O
H
N
R2
R1
C
OH
H2N
R2
Carbonate hydrolysis
O
O
R1
O
C
O
R2
R1
HO
+
OH
Carbonate
O
C
O
HO R2
R2
HO
+
Carbonic acid derivative
C
H
OH
O
C
O
+
O
C
O
+
O
H
O
H
Carbonic acid
Carbamate hydrolysis
O
O
R1
O
C
R2
N
R1
OH
+
HO
C
HN
N
+
HO
R3
R3
Carbamic acid derivative
R3
Carbamate
O
R2
R2
C
H
OH
Carbonic acid
Urea hydrolysis
R1
R2
O
N
C
N
R3
R4
Urea derivative
O
R1
R2
NH
+
HO
C
HN
R1
C
+
R3
R4
Carbamic acid derivative
HO
C
H
O
OH
Carbonic acid
O
O
Hydrazide hydrolysis
N
O
R2
R3
H
N
N
Hydrazide
R2
R3
R1
C
OH
+
H2N
N
R2
R3
Hydrazine
C
O
+
O
H
Drug Examples
OH
O
O
H3C
OH
O
OH
O
+
O
OH
H3 C
CH3
N
H3C
O
O
Salicylic Acid
HO
CH3
O
CH3
N
Cl
N
O
Indomethacin
N
H3C
O
H3C
Slow Hydrolysis
O
HO
O
N
N
N
O
NH2
Prazosin
H2N
CH3
H2 N
OH
N
CH3
O
Rapid Hydrolysis
H
N
N
O
CH3
O
CH3
CH3
Procaine
CH3
Methylecgonine
N
Procainamide
O
O
N
Benzoylecgonine
CH3
CH3
O
O
Cocaine
H
N
H3C
+
O
O
H2N
O
O
Aspirin
O
H3C
OH
Lidocaine
CH3
O
Drug Examples
OH
OH
O
OH
O
+
O
H3 C
O
O
Salicylic Acid
HO
CH3
O
CH3
N
N
O
N
H3C
O
H3C
Slow Hydrolysis
O
HO
O
N
N
N
O
NH2
Prazosin
H2N
CH3
H2 N
OH
N
CH3
O
Rapid Hydrolysis
H
N
N
O
CH3
O
CH3
CH3
Procaine
CH3
Methylecgonine
N
Procainamide
O
O
N
Benzoylecgonine
CH3
CH3
O
O
Cocaine
H
N
H3C
+
O
O
H2N
O
O
Aspirin
H3C
H3C
OH
Lidocaine
CH3
O
Phase II: Drug Conjugation

Attachment of small polar endogenous molecules such as
glucuronic acid, sulfate and amino acids to Phase I metabolites or
parent drugs

Products are more water-soluble and easily excretable

Attenuate pharmacological activity and thus toxicity

Trapping highly electrophilic molecules with endogenous
nucleophiles such as glutathione prevent damage to important
macromolecules (DNA, RNA, proteins)

Regarded as true detoxifying pathway (with few exceptions)

In general, appropriate transferase enzymes activate the
transferring group (glucuronate, sulphate, methyl, acetyl) in a
coenzyme form
Glucuronic Acid Conjugation
•
Glucuronidation is the most common conjugation pathway
•
The coenzyme, UDP glucuronic acid is synthesized from the corresponding
phosphate
•
UDP-glucuronic acid contains D-glucuronic acid in the a-configuration at the
anomeric center, but glucuronate conjugates are b-glycoside, meaning
inversion of stereochemistry is involved in the glucuronidation
•
Glucuronides are highly hydrophilic and water soluble
•
UDP glucuronosyltransferase is closely associated with Cyp450 so that
Phase I products of drugs are efficiently conjugated
•
Four general classes of glucuronides: O-, N-, S-, and C-
•
Neonates have undeveloped liver UDP-glucuronosyltransferase activity, and
may exhibit metabolic problem. For example, chloramphenicol (Chloroptic)
leads neonates to “gray baby syndrome”
Formation of Glucuronide Conjugate
UTP
HO
HO
HO
PPi
O
HO
Phosphorylase
OPO 32a-D-Glucose-1phosphate
HO
HO
HO
O
O
HO
O
O
NH
O P O P O
O-
O-
O
HO
UDPG
N
O
2NAD
U
D
OH PG
+
2N
de
hy
dr
og
en
A
DH
as
e
HOOC
HO
O
HO
O
O
HO
O P O P O
OUDP-Glucuronyl-transferase
(microsomal)
HO
HO
HO
O
RXH
O
XR
HO
b-D-Glucuronide
UDP
O-
O
NH
O
HO
N
O
OH
Uridine-5'-diphosphoa-D-Glucose (UDPG)
Types of Compounds Forming Glucuronides
TYPE
EXAMPLES
CH3
O
H
N
N
CH3
O-Glucuronide
OH
OH
Phenols
O
HO
Acetaminophen
OH
morphine
OH
O
O
OH
H
N
O
Cl
Cl
Alcohols
Chloramphenicol
Enols
Hydroxycoumarine
N-hydroxyamines/amides
CH3
CH3
O
OH
O2 N
H2N
H
N
S
O2
NHOH
Propranolol
CH3
N
OH
N-hydroxydapsone N-Hydroxy-2-acetylaminoflourene
COOH
OH
Aryl acids
Salicylic acid
CH3
O
OH
O
Fenoprofen
Arylalkyl acids
NH2
N-Glucuronides
Arylamines
O
H
N
S
N 7-Amino-5-
Sulfonamides
nitroindazole
O 2N
N
Alkylamines
O
N
H2N
N
O
CH3
N
H
CH3
Sulfisoxazole
H
CH3
3o
Amines
N
CH3
Desipramine
O
NH2
H3C
Amides
O
O
H3C
Meprobamate
NH2
O
Cyproheptadine
N
S-Glucuronides
HS
N
CH3
Sulfhydryl
Methimazole
H3C
S
Carbodithioic acid
H3C
N
SH
Disulfirum (reduced form)
O
C-Glucuronides
N
CH3
N
O
Phenylbutazone
Sulfate Conjugation

Occurs less frequently than does glucuronidation presumably due to
fewer number of inorganic sulfates in mammals and fewer number of
functional groups (phenols, alcohols, arylamines and N-hydroxy
compounds)

Three enzyme-catalyzed reactions are involved in sulfate conjugation
O
-
ATP
O
-
-
O S O
O
Sulfate
PPi
Mg+2
ATP sulfurylase
O
O
O S O P O
O
-
O
O
Ad
ATP
ADP
-
O
O S O P O
O
-
O
+2
Mg
APS phosphokinase
HO
OH
Adenosine-5'phosphosulfate (APS)
O
Ad
RXH
PAP
O
Sulfotransferase
(soluble)
-2
O3 PO
OH
3'-phosphoadenosine-5'phosphosulfate (PAPS)
-
O S XR
O
Sulfate
conjugate
Sulfation of Drugs

Phenolic sulfation predominates

Phenolic O-glucuonidation competes favorably with sulfation due to limited
sulfate availability

Sulfate conjugates can be hydrolyzed back to the parent compound by
various sulfatases

Sulfoconjugation plays an important role in the hepatotoxicity and
carcinogenecity of N-hydroxyarylamides

In infants and young children where glucuronyltransferase activity is not
well developed, have predominating O-sulfate conjugation

Examples include: a-methyldopa, albuterol, terbutaline, acetaminophen,
OH
H
phenacetin
HO
OH
H
HO
N
H3C
HO
H
COOH
HO
a-Methyldopa
H
N
HO
Albuterol
N
CH3
CH3
CH3
CH3
CH3
CH3
OH
Terbutaline
Amino Acid Conjugation

The first mammalian drug metabolite isolated, hippuric acid, was the
product of glycine conjugation of benzoic acid
R
O
COH
Benzoic Acid, R = H
Salicylic Acid, R = OH
R
O
O
CONHCH2COH
Hippuric Acid, R = H
Salicyluric Acid, R = OH

Amino acid conjugation of a variety of caroxylic acids, such as aromatic,
arylacetic, and heterocyclic carboxylic acids leads to amide bond formation

Glycine conjugates are the most common

Taurine, arginine, asparagine, histidine, lysine, glutamate, aspartate,
alanine, and serine conjugates have also been found
Mechanism of Amino Acid conjugation
Drug-COOH
An Acyl-CoA Intermediate
Glycine Conjugate R = H
Glutamine Conjugate R = CH2CH2CONH2
Brompheniramine Metabolism
N
CH3
N
CH3
CH3
NH
N
P450
NH2
N
P450
Br
Brompheniramine
Br
N
CHO
N
P450
Br
H
N
N
O
Br
Brompheniramine N-oxide
COOH
Aldehyde
dehydrogenase
Br
CH3
N
CH3
N
Br
Glycine conjugate
Br
Carboxylic Acid metabolite
Glycine
N-acyltransferase
COOH
Glutathione Conjugation
NH 2
H
N
HO
O
HO
HS
H
N
O
O
N
H
O
OH
O
O
O
O
O
N
H
S
S
H
N
NH 2
HO
NH 2
Glutathione reduced form (GSH)
N
H
OH
O
O
OH
O
Glutathione oxidized form (GSSG)
•
Glutathione is a tripeptide (Glu-Cys-Gly) – found virtually in all
mammalian tissues
•
Its thiol functions as scavenger of harmful electrophilic parent drugs
or their metabolites
•
Examples include SN2 reaction, SNAr reaction, and Michael addition
SN2 Examples
GSH
R X SG + Y
GlutathioneS-Transferase
A.
SN2
R X Y
-
1. CH3O2SO
Busulfan
OSO2CH3
ONO2
2.
H
ONO2
SG
X = C, O, S; Y = leaving group or epoxide
CH3O2SO
ONO2
-
SG
O NO2
H
SG
S+ G
ONO2
ONO2
-
SG H
O SG
ONO2
+ GSSG
OH
Nitroglycerine
CH 3
O
O
CH3
O
Naproxcinod
O
O
N
O
SNAr Examples
X
SG
GSH
B.
SNRr
Z
Z
N
1.
N
O
+
N O
S
H3C
N
-
N
-
SG
N
N
N
H
Azathioprine
O
+
N OSG
S
N
H3C
N
N
N
N
N
H
N
SH
NO2
+
N
N
SG
H3C
N
N
1-Methyl-4-nitro-5H
(S-glutathionyl) 6-Mercaptopurine
imidazole
Michael Addition
H+
C.
-
Z
SG
Z
SG
Michael Addition
CH3
N
CH3
N
CH3
N
SG
-
SG
HO
O
OH
HO
O
O
CH3
SG N
O
O
O
HO
GS
OH HO
OH
CH3
N
O
OH
Mercapturic Acid Conjugates
Drug
O
HO
S
H
N
O
O
O
Amino Acid
-Glutamyl-AA
(AA)
OH
N
H
NH 2
 -Glutamyl
transpeptidase
Drug
O
HO
S
H
N
NH 2
O
Glutathione Conjugate
Drug
Glycine
Cysteinyl
Glycinase
Acetyl
CoA
S
HO
NH 2
O
S-substituted
Cysteine
Derivative
CoASH
Drug
S
H 2N
O
N
H
O
Mercapturic
acid conjugate
CH 3
Acetyl Conjugation

Metabolism for drugs containing a primary amino group, (aliphatic and aromatic
amines), amino acids, sulfonamides, hydrazines, and hydrazides

The function of acetylation is to deactivate the drug, although Nacetylprocainamide is as potent as the parent antiarrhythmic drug procainamide
(Procanbid) or more toxic than the parent drug, e.g., N-acetylisoniazid

Acetylation is two-step, covalent catalytic process involving N-acetyl transferase
O
H3 C
X-
O
CoASH
SCoA
H3 C
O
X
H2N
N-Acetylation of amines
R
H3 C
NHR
X-
Example of Acetylated Drugs
O
O
HO
S
NH
O
OH
NH2
CH3
CH3
Cilastatin
HO
H3 C
N
S
H
N
O
COOH
Imipenem
NH
Methyl Conjugation

Minor conjugation pathway, important in biosynthesis of epinephrine
and melatonin; in the catabolism of norepinephrine, dopamine,
serotonin, and histamine; and in modulating the activities of
macromolecules (proteins and nucleic acids)

Except for the formation of quarternary ammonium salts, methylation
of an amine reduces the polarity and hydrophilicity of the substrates

A variety of methyl transferase, such as COMT (catechol O-methyl
transferase), phenol-O-methyltransferase, N-methyl transferase, Smethyltransferase etc are responsible for catalyzing the transfer of
methyl group from SAM to RXH
H2 N
COOH
H2N
ATP
H2 N
COOH
PPi + Pi
Methyltransferase
H3CS
Methionine
adenosyltransferase
+
S
O
Mthetionine
HO
Ad
CH3
HX-R
OH
S-Adenosylmethionine
Mechanism of methyl conjugation
CH3 -X-R
COOH
+
S
O
HO
Ad
OH
Factors influencing Drug
Metabolism
83
Factors influencing Drug Metabolism


1-Chemical Structure :
The chemical structure (the absence or presence of certain functional groups) of
the drug determines its metabolic pathways.


2-Species differences (Qualitative & Quantitative):
Qualitative differences may result from a genetic deficiency of a certain enzyme
while quantitative difference may result from a difference in the enzyme level.


3-Physiological or disease state:
1-For example, in congestive heart failure, there is decreased hepatic blood flow
due to reduced cardiac output and thus alters the extent of drug metabolism.
2-An alteration in albumin production can alter the fraction of bound to
unbound drug, i.e., a decrease in plasma albumin can increase he fraction of
unbound free drug and vice versa.
3-pathological factors altering liver function can affect hepatic clearance of the
drug.


Factors influencing Drug Metabolism
 4-Genetic variations:

Isoniazid is known to be acetylated by N-acetyltransferase into
inactive metabolite.

The rate of acetylation in asian people is higher or faster than that
in eurpoean or north american people. Fast acetylators are more
prone to hepatoxicity than slow acetylator.
 5-Drug dosing:

1- An increase in drug dosage would increase drug concentration
and may saturate certain metabolic enzymes.

2- when metabolic pathway becomes saturated, an alternative
pathway may be pursued.
85
Factors influencing Drug Metabolism
6-Nutritional status:

1-Low protein diet decreases oxidative reactions or conjugation reactions due to
deficiency of certain amino acids such as glycine.

2-Vitamin deficiency of A,C,E, and B can result in a decrease of oxidative
pathway in case of vitamin C deficiency , while vitamin E deficiency decreases
dealkylation and hydroxylation.

3-Ca, Mg, Zn deficiencies decreases drug metabolism capacity whereas Fe
deficiency increases it.

4-Essential fatty acid (esp. Linoleic acid) deficiency reduce the metabolism of
ethyl morphine and hexobarbital by decreasing certain drug-metabolizing
enzymes.
Factors influencing Drug Metabolism
7-Age:
1- Metabolizing enzymes (sp.glucuronide conjugation)are not fully
developed at birth, so infants and young children need to take
smaller dosesthan adults to avoid toxic effects.
2-In elderly, metabolizing enzyme systems decline.
8-Gender (sex):
Metabolic differences between females and males have been observed
for certain compounds
Metabolism of Diazepam, caffiene, and paracetamol is faster in females
than in males while oxidative metabolism of lidocaine,
chordiazepoxide are faster in men than in females
Factors influencing Drug Metabolism
9-Drug administration route:

1-Orally administered drugs are absorbed from the GIT and
transported to the liver before entering the systemic circulation.
Thus the drug is subjected to hepatic metabolism (first pass
effect) before reaching the site of action.

2-Sublingually and rectally administered drugs take longer time
to be metabolized than orally taken drugs.Nitroglycerine is
ineffective when taken orally due to hepatic metabolism.

3-IVadministration avoid first pass effect because the drug is
delivered directly to the blood stream.
Factors influencing Drug Metabolism
10-Enzyme induction or inhibition
Several antibiotics are known to inhibit the activity of cytochrome P450.
Phenobarbitone is known to be cytochrome P450 enzyme inducer while
cimetidine is cyt. P450 inhibitor.
If warfarin is taken with phenobarbitone, it will be less effective.
While if it is taken with cimetidine, it will be less metabolized and thus serious
side effects may appear.
Study Guide
1. What Roles are Played by Drug Metabolism? Know with structural
examples
2. Role of stereochemistry in metabolism of drugs with example of warfarin,
ibuprofen and itomidate
3. What is first pass effect; enterohepatic circulation? Why and how they
occur? Drug examples
4. Metabolisms in the intestinal mucosa
5. CYP450, Hepatic microsomal flavin containing monooxygenases (MFMO
or FMO) Monoamine Oxidase (MAO) and Hydrolases. Drugs metabolised
by these enzymes and the active sites of these enzymes. Types of
metabolic reaction catalyzed by these enzymes
6. Specific CYP enzymes with the number of drugs they metabolize
7. Few CYP family with their main functions
8. Drug interaction basics related to metabolic enzymes
Study Guide Cont.
9. Mechanism and routes of aromatic hydroxylation. The effects of electron
donating and withdrawing groups in aromatic hydroxylation. Drug examples.
What is NIH shift?
10. Oxidation of olefins. Role of epoxide hydrolase. Can olefenic epoxide be
converted to alcohol as in aromatic epoxide by NIH shift?
11. What type of C in a drug molecule can not be hydroxylated?
12. What is allylic and benzylic hydroxylation? Show drug examples.
13. Show the drug examples where hydroxylation occur on Cα to C=O and C=N
bonds
14. Show the drug examples where hydroxylation occur at aliphatic and alicyclic
carbon atoms. Which carbons are more easily hydroxylated?
15. What is N-oxidatin and N-dealkylation. What enzymes are involved? How do
you differentiate between N-dealkylation and deamination. Drug examples.
What types of drugs generates lactams instead of causing dealkylation?
16. What is the difference between mixed function oxidases and amine oxidases?
Study Guide Cont.
17. What is the difference between ethanol oxidation and O-dealkylation?
18. What is S-dealkylation, desulfuration and S-oxidation? Drug examples.
19. How does steric factors influence S- O- and N-dealkylations?
20. Oxidative dehalogenation with special example of chloramphenicol. Why
chloramphenicol cause toxicity to the babies?
21. What is MFMO and its active site? What types of functional groups are
metabolized by this enzyme? Drug examples.
22. MAO, dehydrogenases, xanthene oxidases and their functions with drug
examples. Difference between MAO-A and MAO-B.
23. Alcohol and aldehyde dehydrogenases, the coenzymes and the types of drugs
they work on.
24. Azo and nitro reductases, their coenzymes and the drugs they act on.
Study Guide Cont.
25. Different types of hydrolytic enzymes. Compare rate of hydrolysis of esters,
amides, carbonates and carbamates.
26. What are different types of conjugation reactions?
27. The enzymes and substrates involved in glucuronidation, and sulfate
conjugation.
28. Why acetaminophen is toxic to neonates? Mechanism of phenacetin and
acetaminophen toxicity.
29. What types of drugs or metabolites may form glycin conjugates?
30. What are different mechanisms involved in glutathione conjugation? What is
mercapturic acid conjugate? Mercapturic acid conjugate of acetaminophen is a
sign of its toxicity – why?
31. Mechanism of acetylation. What is slow and fast acetylator?
32. What is COMT? What coenzymes is involved in its action? What types of drugs
and/or neurotransmitters are metabolized by COMT?
THANK YOU
-PHARMA STREET