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Metabolism I
1. Kailas K Mali
HOD, Pharmaceutics
Yashoda Technical Campus,
Faculty of Pharmacy,
Satara
2. Contents
Introduction
Drugs metabolizing enzymes
Chemical pathways of drug biotransformation
Phase I reaction
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3. How Drug go out from body ?
Drug Elimination
Metabolism:
conversion of one
chemical
entity to another.
Excretion:
Loss of drug or its
metabolites
4. The main routes by which drugs and
their metabolites leave the body are:
-Kidney
-Hepatobiliary system
-Lungs
• Most drugs leave the body in the urine,
either unchanged or as polar metabolites
• Some drugs are secreted into bile via the
liver
• But most are reabsorbed from the intestine .
5. Introduction
Elimination
Irreversible loss of drug from the body
Generally it is occurs by two processes
Biotransformation
Excretion
Biotransformation
Chemical conversion of one form to another
Example:
Conversion of penicillin to penicilloic acid by the bacterial
penicillinase
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6. Introduction
Biotransformation
Drug metabolism (biotransformation or detoxication) is
the biochemical changes of the drugs and other foreign
substances in the body.
This is leading to the formation of different metabolites with
different effects.
Some of the compounds are excreted partially unchanged and
some are known to be converted to products, which may be
more active or more toxic than the parent compounds.
The liver is the major site of drug metabolism, but specific
drugs may undergo biotransformation in other tissues.
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7. Introduction
Biotransformation: Importance
Drug metabolism is needed to convert non-polar
lipophilic compounds (lipid soluble) which the body
cannot excrete into more polar hydrophilic compounds
(water soluble) which the body can excrete them in
short period of time.
Because if the lipid soluble non-polar compounds are
not metabolized to the polar water soluble compounds,
they will remain in the blood and tissues and maintain
their pharmacological effects for an indefinite time.
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9. Classification of Metabolism
Inactive metabolites
Metabolites retain similar activity
Metabolites with different activity
Bioactivated metabolites (prodrug technique)
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10. Classification of Metabolism
Inactive metabolites
Conversion of active compound to pharmacologically
inactive
Oxidation of 6-mercaptopurine to 6-mercapturic acid results in
loss of anticancer activity of this compound.
6-Mercaptopurine 6-Mercapturic acid (inactive)
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11. Classification of Metabolism
Metabolites retain similar activity
Some metabolite retain the pharmacological activity of their parent
compounds to a greater or lesser degree.
Codeine is demethylated to the more active analgesic morphine
Phenacetin is metabolized to more active paracetamol
Imipramine is demethylated to the equiactive antidepressant
desipramine.
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12. Classification of Metabolism
Metabolites with different activity
Some metabolites develop activity different from that of their
parent drugs.
Iproniazid (antidepressant) is dealkylated to isoniazid
(antitubercular)
Retinoic acid (vitamin A) is isomerized to isoretinoic acid (anti-
acne agent).
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13. Classification of Metabolism
Bioactivated metabolites (prodrug technique)
Some inactive compounds are converted to active drugs within the
body.
These compounds are called prodrugs.
Prodrugs may have advantages over the active form (active
metabolite) as more stable, having better bioavailability or less side
effects and toxicity.
Levodopa (antiparkinson disease) is decarboxylated in the neuron
to active dopamine.
The prodrug sulindac a new non steroidal antiinflammatory drug
(sulfoxide) is reduced to the active sulfide
Benorylate to aspirin and paracetamol
The prodrug enalapril is hydrolysed to enalaprilat (potent
antihypertension).
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14. Biotransformation
Pharmacological inactivation of drug
Formation of metabolite with little pharmacological action
Phenytoin p- Hydroxy phenytoin
Yield metabolite with equal activity
Phenylbutazone Oxyphenbutazone
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15. Biotransformation
Rarely leads to toxicological activation of drugs
Paracetamol N- hydroxylated metabolite
(causes hepatic necrosis)
Inactive drugs (prodrugs) also depend upon
biotransformation for activation process called as
pharmacological activation.
Chloramphenicol Palmitate Chloramphenicol
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16. Metabolite
activity
Examples and notes
Inactive
(detoxification)
Similar activity
to the drug
Different
activity
Toxic
metabolites
N
N
O
Ph
Cl
CH3
N
N
O
Ph
Cl
CH3
OH
N
H
N
O
Ph
Cl
Diazepam
(Sustained anxiolytic action)
Hydroxylation
Temazepam
(Short duration)
Oxazepam
(short duration)
N-Demethylation OH
N
CONHNHCH
CH3
CH3
N
CONHNH2
Ipronazid
(Antidepressant)
N-Dealkylation
Isoniazid
(Antituberculosis)
NCOCH3
HO
OC2H5
NHCOCH3
OC2H5
NH2
OC2H5
N-Hydroxyphenacetin
(Hepatotoxic)
Phenacetin
(Analgesic)
Phenetidine
Substances responsible
for methemoglobinamia
Other substances
responsible for
hepatotoxicity
OH
Phenol
Phenol sulphokinase
3'-Phosphoadenosine-5'-
phosphosulfate (PAPS)
O
S
O
O OH
Phenyl hydrogen sulfate
Routes that result in the formation of inactive metabolites are often referred to as detoxification.
The metabolite may exhibit either a different potency or duration of action or both to the
original drug.
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17. Stereochemistry of Drug Metabolism
O
CH2COCH3
Ph
H
OH
O
O
CH2COCH3
Ph
H
OH
O O
H2C
H
Ph
OH
O
OH
CH3
H
O
CH2COCH3
H
Ph
OH
O
O
H2C
H
Ph
OH
O
OH
H
CH3
S-(-)-Warfarin
S-6-Hydroxywarfarin
R-(+)-Warfarin
Major route
Minor route
R,S-(+)-alcohol derivative R,R-(+)-alcohol derivative
HO
CH3
H
COOH
COOH
H
CH3
Metabolism
R-(-)-Ibuprofen
(inactive)
S-(+)-Ibuprofen
(active)
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18. Stereochemistry of Drug Metabolism
N
P
O
O
NHCH2CH2Cl
CH2CH2Cl
N
P
O
O
NH2
CH2CH2Cl
NH
P
O
O
NHCH2CH2Cl
R-Ifosfamide
R-2-Dechloroethylifosfamide
S-3-Dechloroethylifosfamide
+
ClCH2CHO
Chloroacetaldehyde
(Neurotoxic)
N
P
O
O
H2N
ClH2CH2C
HN
P
O
O
ClH2CH2CHN
S-2-Dechloroethylifosfamide
R-3-Dechloroethylifosfamide
+
ClCH2CHO
Chloroacetaldehyde
(Neurotoxic)
N
P
O
O
ClH2CH2CHN
ClH2CH2C
S-Ifosfamide
CYP2B6
CYP2B6
CYP3A4
CYP3A4
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19. Drug metabolizing enzymes
Enzymes
Differs from those that metabolize food materials
Two types
Microsomal enzymes
Non-Microsomal enzymes
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20. Drug metabolizing enzymes
Microsomal
Catalyze majority of drug biotransformation reactions, are derived
from rough endoplasmic reticulum.
Catalyzes oxidative, reductive, hydrolytic and glucuronidation
reactions
Lipoidal nature leads to selectivity towards lipid soluble substrate
Do not interact with natural endogenous substances, which are
water soluble
Lipid soluble substrate Water soluble
metabolite
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21. Drug metabolizing enzymes
Non Microsomal enzymes
Non specific enzymes present in soluble form in cytoplasm
attached to mitochondria,
Act on water soluble xenobiotics
Oxidases, peroxidases, esterase etc.
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22. Biotransformation Pathways
Drug metabolism reactions have been divided into two
classes:
Phase I reaction (functionalization ) and
Phase II reaction (conjugation)
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23. General Metabolic Pathways
Glucuronic acid conjugation
Sulfate Conjugation
Glycine and other AA
Glutathion or mercapturic acid
Acetylation
Methylation
Reduction
Aldehydes and ketones
Nitro and azo
Miscellaneous
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
Phase II -
Conjugation
Phase I -
Functionalization
Drug
Metabolism
Hydrolytic Reactions
Esters and amides
Epoxides and arene oxides
by epoxide hydrase
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24. Phase I Reaction
Polar functional groups are either
introduced into the molecule
or modified by oxidation, reduction or hydrolysis.
or convert lipophilic molecules into more polar molecules by
introducing or exposing polar functional groups.
Aromatic and aliphatic hydroxylation or reduction of ketones and
aldehydes to alcohols.
Phase I reactions may increase or decrease or leave unaltered the
pharmacological activity of the drugs
Objectives
Increase in hydrophilicity
Reduction in stability
Facilitation of conjugation
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25. Phase I Reaction
Reactions in Phase I Metabolism
Oxidation reaction
Reduction
Hydrolysis
Hydration
Isomerisation
Miscellaneous
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26. Phase I Reaction
Enzymes catalyzing phase I reactions include
cytochrome P-450
aldehyde and alcohol dehydrogenase
deaminases
esterases
amidases
epoxide hydratases
Location of these enzymes
numerous tissues
some are present in plasma.
Subcellular locations include
cytosol
mitochondria
endoplasmic reticulum
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27. Cytochrome P 450 Monooxygenase
General features
A large number of families (at least 18 in mammals) of cytochrome
P-450 (abbreviated “CYP”) enzymes exists
each member of which catalyzes the biotransformation of a unique
spectrum of drugs.
some overlap in the substrate specificities.
This enzyme system is the one most frequently involved in phase I
reactions.
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28. Cytochrome P 450 Monooxygenase
General features
The cytochrome P-450 families are referred to using an arabic
numeral, e.g., CYP1, CYP2, etc.
Each family has a number of subfamilies denoted by an upper
case letter, e.g., CYP2A, CYP2B, etc.
The individual enzymes within each subfamily are denoted
by another arabic numeral, e.g., CYP3A1, CYP3A2, etc.
Cytochrome P-450 catalyzes numerous reactions, including:
aromatic and aliphatic hydroxylations
dealkylations at nitrogen, sulfur, and oxygen atoms
heteroatom oxidations at nitrogen and sulfur atoms
reductions at nitrogen atoms
ester and amide hydrolysis
4/13/2018 28
29. Cytochrome P 450 Monooxygenase
General features
The CYP3A subfamily is:
responsible for up to half of the total cytochrome P-450 in the
liver
accounts for approximately 50% of the metabolism of
clinically important drugs.
CYP3A4 is a particularly abundant enzyme.
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31. Cytochrome P 450 Monooxygenase
Cytochrome P450
The primary location of cytochrome P-450 is the liver,
Other tissues, including:
the adrenals
ovaries and testis
tissues involved in steroidogenesis and steroid metabolism.
The enzyme's subcellular location is the endoplasmic reticulum.
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32. Cytochrome P 450 Monooxygenase
Cytochrome P450
Name based on its light absorption at 450 nm when complexed with
carbon monoxide
Hemoprotein (heme-thiolate) containing an iron atom which can
alternate between the ferrous (Fe++) and ferric (Fe+++) states
Electron acceptor
Serves as terminal oxidase
N N
NN
CH3
HOOC
HOOC
CH3 CH3
CH2
CH3
CH2
Fe+3
L
O
H R
Substrate binding site
Heme portion
with activated
Oxygen
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33. Cytochrome P 450 Monooxygenase
Mechanism of reaction
In the overall reaction:
the drug is oxidized
oxygen is reduced to water.
Reducing equivalents are provided by nicotinamide adenine
dinucleotide phosphate (NADPH), and generation of this
cofactor is coupled to cytochrome P-450 reductase.
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34. Oxidation Reaction
Addition of oxygen or removal of hydrogen.
Normally the first and most common step involved in the drug
metabolism
Majority of oxidation occurs in the liver and it is possible to occur in
intestinal mucosa, lungs and kidney.
Most important enzyme involved in this type of oxidation is
cytochrome P450
Increased polarity of the oxidized products (metabolites) increases
their water solubility and reduces their tubular reabsorption, leading
to their excretion in urine.
These metabolites are more polar than their parent compounds and
might undergo further metabolism by phase II pathways
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35. Oxidation Reaction
Catalysed by microsomal enzymes
Require both molecular oxygen and reducing agent
NADPH, they are referred to as mixed function oxidases
(MFO).
MFO consists of 3 components
Cytochrome P450- heme protein, transfer of oxygen atom
Flavoprotein- NADPH dependent, acts as electron carrier, catalyze
the reduction of Cytochrome P450
Phosphatidylcholine- facilitate electron transfer
RH + O2 + NADPH + H+ ROH + H2O + NADP+
4/13/2018 35
37. Electron flow in microsomal drug oxidizing system
CO
hu
CYP-Fe+2
Drug
CO
O2
e-
e-
2H+
H2O
Drug
CYP
R-Ase
NADPH
NADP+
OHDrug
CYP Fe+3
PC
Drug
CYP Fe+2
Drug
CYP Fe+2
Drug
O2
CYP Fe+3
OHDrug
4/13/2018 37
38. Oxidation Reaction
Oxidation of aromatic carbon atoms
Oxidation of olefins (C=C)
Oxidation of Allylic carbon atom
Oxidation of Alicyclic carbon atom
Oxidation of Carbon- hetero atom
Oxidation of Carbon – Nitrogen system
N- dealkylation
Oxidative deamination
N- oxide formation
N- hydroxylation
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39. Oxidative Reactions
OH O
C C
O
C C
C H
C OH
O C
O P
S C
S P S CH3
SH, S CH3
O
R O CH3
R OH
R N H
R N
R N CH2R
R N
R N OH
R NH
O
CHRO
"Activated Oxigen"
[FeO]
3+
Arene OxidesArenols
Epoxides
Benzylic, allylic
aliphatic C
Hydroxylation
Miscellaneous
Oxidations +
Desulfuration
S-Dealkylation
and S-Oxidation
O-Dealkylation N-Hydroxylation
N-Dealkyaltion and
Oxidative Deamination
N-Oxide Formation
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40. Oxidation of aromatic carbon atom
Aromatic Hydroxylation
Mixed function oxidation of arenes to arenols via an epoxide
intermediate arene oxide
Major route of metabolism for drugs with phenyl ring occurs
primarily at para position
Substituents attached to aromatic ring influence the
hydroxylation
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
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41. Oxidation of aromatic carbon atom
Aromatic Hydroxylation
N
N
O
H
H
O N
N
O
H
H
O
CYP2C19
HO
Phenytoin to p-hydroxyphenytoin
R
O
Spontaneous
Rearrangement
R
-
O H
H+
NIH Shift
R
O
H
H
R
OH
Arenol
Arene Oxide
4/13/2018 41
42. Oxidation of aromatic carbon atom
Para- hydroxylated product is most common
Acetanilide Paracetamol
Oxidation
Aromatic Hydroxylation
4/13/2018 42
43. EpoxideAlkene trans dihydrodiol derivative
Epoxide hydrolaseO OHOH
■ 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 hydrase to form trans-1,2-
dihydrodiols (also called 1,2-diols or 1,2-dihydroxy compounds)
■ Terminal alkenes may form alkylating agents following this pathway
NH2O
N
NH2O
N
NH2O
N
Epoxide hydrolaseCYP3A4
O HO OH
Carbamazepine Carbamazepine 10,11 epoxide Carbamazepine trans 10,11 diol
(Active) (Active & Toxic) (Inactive)
Oxidation of Olefins (Alkenes)
4/13/2018 43
44. Oxidation of Allylic carbon atom
Hexobarbital
3’
2’
OH
Hydroxylation
3’- Hydroxy hexobarbital
4/13/2018 44
45. Oxidation of carbon atoms alpha to carbonyls and Imines
Diazepam to 3 hydroxy desmethyldiazepam
4/13/2018 45
46. Oxidation of Alicyclic Carbon Atom
■ 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
H3C
O
OOO
N
H
N
H
S
H3C
O
OOO
N
H
N
H
S
CYP450
OH
Acetohexamide Metabolism
4/13/2018 46
47. Oxidation of Alicyclic Carbon Atom
Minoxidil 4’- Hydroxy Minoxidil
Hydroxylation
4/13/2018 47
48. Oxidation of Carbon - Hetero Atoms
Biotransformation of C-N, C-O and C-S system proceeds in
two ways:
Hydroxylation of carbon atom attached to heteroatom e. g. N-, O-
and S- dealkylation, oxidative deamination and desulphuration
Oxidation of heteroatom itself
4/13/2018 48
49. Oxidation of carbon- nitrogen system
N- Dealkylation
Oxidation of alpha- carbon atom to generate an intermediate
carbinolamine rearranges by cleavage of C-N bond to yield N-
Dealkylated product and carbonyl of alkyl group.
Tertiary nitrogen>sec. nitrogen favors dealkylation due to high lipid
solubility
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51. Oxidative Deamination
Cleavage occurs at bond between amino group link to
larger portion of drug molecule. Formed amines are
simple.
Primary aliphatic amines undergo deamination
Phenyl acetone
+ NH3
AmmoniaAmphetamine
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55. Oxidation of Carbon- sulphur system
■ S-Dealkylation
■ Desulfuration
■ S-Oxidation
C S R3R1 C SR1 C OR1 HS R3+
R2R2
OHH
R2
R3
CYP450 Spontaneous
Steric hindrance discussion similar to N-dealkylation
R1 C R2
S
R1 C R2
O
R1 S R2 R1 S R2
O
R1 S R2
O
O
Sulfoxide Sulfone
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56. Oxidation of Carbon- sulphur system
S- Dealkylation
N
N
S
CH3
N
H
N
6-(Methylthio)-purine
N
N
S
CH2
N
H
N
OH
N
N
SH
N
H
N
CH2
O
6-Mercaptopurine
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58. Oxidation of Carbon- sulphur system
S Oxidation
CH3
S
CH3
NN
S
CH3
S
CH3
NN
S
CH3
S
CH3
NN
S
CH3S
CH3
NN
S
CH3
S
CH3
NN
S
O
O
O
O O O
Thioridazine
Ring Sulfoxide Ring Sulfone
Mesoridazine Sulforidazine
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59. Oxidation of Carbon- oxygen system
O- Dealkylation
C O R3 HO R3+
H
R1
R2
C O R3
OH
R1
R2
CYP450 Spontaneous
R1 C
R2
O
■ Converts an ether to an alcohol plus a ketone or aldehyde
■ Steric hindrance discussion similar to N-dealkylation
4/13/2018 59
60. Oxidation of Carbon- oxygen system
O- Dealkylation
O
O
O
NH2
NH2
N
N
CH3
H3C
H3C
O
O
O
NH2
NH2
N
N
CH2
H3C
H3C
OH
O
O
NH2
NH2
N
N
H3C
H3C
OH
Spontaneous
CYP450
Trimethoprim O-Dealkylation
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61. Oxidation of Carbon- oxygen system
O- Dealkylation
Codeine Morphine
4/13/2018 61
62. Oxidative Dehalogenation
O- Dehalogenation
R C
H
Cl
Cl
R C
OH
Cl
Cl
R C
O
Cl
R C
O
OH
+
H Cl
+H2O
CYP450
H Cl
+
Spontaneous
• Requires two halogens on carbon
• With three there is no hydrogen available to replace
• With one, the reaction generally won’t proceed
• The intermediate acyl halide is very reactive
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64. Hepatic Microsomal Flavin Containing Monooxygenases
C
H3C
NH N
S
H
N
H
N
CH3
N
N
C
H3C
NH N
S
H
N
H
N
CH3
N
NO
MFMO
• 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
Cimetidine MFMO S-Oxidation
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65. Oxidation catalysed by other enzymes
Alcohol dehydrogenase
A soluble enzyme, found almost exclusively in the
parenchymal cells of the liver
Converts ethanol to acetaldehyde
Converts methanol to formaldehyde
Converts ethylene glycol to its respective aldehyde
metabolites
Is inhibited by pyrazole
CH3CH2OH + NAD+ CH3CHO + NADH + H+
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66. Oxidation catalysed by other enzymes
Aldehyde dehydrogenase
Found primarily in the liver. Oxidizes free aldehydes and has
broad substrate specificity
Is inhibited by disulfiram
Mitochondrial enzyme
involved in the metabolism of acetaldehyde
Cytosolic enzyme
oxidizes xenobiotic aldehydes
Microsomal enzyme
oxidizes xenobiotic aldehydes
CH3CHO + NAD+ CH3COOH + NADH + H+
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67. Oxidation catalysed by other enzymes
Xanthine oxidase
This enzyme specifically oxidizes xanthine containing drugs
Theophylline
O
HN
N
N
H
N
H
O
O
HN
N
N N
H
O
HN
N
N
H
N
H
O
OH
O
HN
H
N
N
H
N
H
O
O
Hypoxanthine Xanthine Uric acid
(hydroxy tautomer)
Uric acid
(keto tautomer)
Xanthine
oxidase
Xanthine
oxidase
4/13/2018 67
68. Oxidation catalysed by other enzymes
Amine oxidase (N oxidation)
This enzyme specifically oxidizes xanthine containing drugs
Imipramine (require NADPH and molecular oxygen)
4/13/2018 68
69. 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
4/13/2018 69
70. Reductive Reactions
Reduction of N- compounds
Nitro- reduction
Azo- reduction
N- oxide
Reduction of Aldehydes/ ketones
Reduction of Alcohols and C=C bond
Miscellaneous Reductive Reactions
Reductive Dehalogenation
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71. Reductive Reactions
Nitro and Azo Reduction
N NR
Azido
NH2R
Amine
NH + N N
N2
N N R2R1 R1 NH2 H2N R2+
Azo Two 1 amines
H
NR1
Hydrazo
H
N R2
R C N
H
H
R C N
H
H
H
H
H
OH
R C N
H
H
R C N
H
H
O
O
1 amineHydroxylamineNitrosoNitro
O
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72. Reductive Reactions
Nitro and Azo Reduction
• 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
reduces the azo
• Bacterial reductases in intestine can reduce both nitro and azo
4/13/2018 72
74. Reductive Reactions
Reduction of Carbonyls
Depending on reactivity towards bioreduction,
carbonyls can be divided into 3-
Aliphatic aldehydes and ketones
Aromatic aldehydes and ketones
Esters, acids and amides
The order of reactivity is i > ii> iii
Reduction of i and ii yields primary and sec. alcohols.
4/13/2018 74
75. Reductive Reactions
■ Reduction of Carbonyls
■ 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
4/13/2018 75
76. Reductive Reactions
• Reduction of Carbonyls
• 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
R C O
H
R C
H
OH
H
Aldehyde 1 alcohol
R C O
R2
R1 C
R2
OH
H
Ketone 2 alcohol
4/13/2018 76
78. Reduction of Carbonyls
Reduction of Aliphatic Ketones
R1
C
R2
O
N
R
H
H
H2N
OH
+
R1
C
R2
HO H
+
N
+
R
H2N
O
Ketone Chiral AlcoholRed Nicotinamide moiety
of NADPH or NADH
Ox Nicotinamide moiety
of NADP
+
or NAD
+
4/13/2018 78
82. 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
Differs from oxidative and reductive reactions in 3 respects
Does not involve change in the state of oxidation of substrate
Results in large chemical change in substrate, loss of large fragment
Hydrolytic enzymes acts on endogenous substrate
Hydrolysis of esters and ethers
Hydrolysis of amides
Hydrolytic Dehalogenation
4/13/2018 82
83. Hydrolytic Reactions
■ 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
R1 R2 Name Susceptibility
to Hydrolysis
C O Ester Highest
C S Thioester
O O Carbonate
C N Amide
O N Carbamate
N N Ureide Lowest
Naming carbonyl - heteroatom groups
R1 C R2
O
+
4/13/2018 83
84. Hydrolytic Reactions
R1 C
O
H
N R2 R1 C
O
OH H2N R2
O C O R2R1
O
HO C O R2R1
O
OH HO C OHR2
O
HO O C O O H
H
+++
Carbonate Carbonic acid derivative Carbonic acid
Ester hydrolysis
Amide hydrolysis (slower)
Carbonate hydrolysis
R1 C
O
O R2 R1 C
O
OH HO R2
4/13/2018 84
85. Hydrolytic Reactions
O C NR1
O
HO C NR1
O
OH HO C OH
O
HN O C O O H
H
+++
Carbamate Carbamic acid derivative
Carbonic acid
R2
R3
R2
R3
R2
R3
N C N
O
HO C N
O
NH HO C OH
O
HN O C O O H
H
+++
Urea derivative Carbamic acid derivative
Carbonic acid
R3
R4
R3
R4
R2
R3
R1
R2
R1
R2
R1 C
H
N N
O
R2
R3
R1 C OH
O
H2N N
R2
R3
+
Hydrazide Hydrazine
Carbamate hydrolysis
Urea hydrolysis
Hydrazide hydrolysis
4/13/2018 85
87. Hydrolysis of esters
Organic acid esters
H3C O
O
O
OH
H3C O
OH
O
OH
OH
+
Aspirin Salicylic Acid
4/13/2018 87
88. Hydrolysis of esters
Inorganic acid esters
4/13/2018 88
CH3
CH3 C O S CH3
H O
O CH3
CH3 C OH
H
HO S CH3
O
O
+
Isopropyl methane
sulphonate
Isopropanol Methanesulponic
acid
89. Hydrolysis of esters
Hydrolysis of Amide (C-N bond cleavage)
Reaction catalysed by amidases
Cleavage yield carboxylic acid and amine
R1 C
H
N N
O
R2
R3
R1 C OH
O
H2N N
R2
R3
+
Hydrazide Hydrazine
4/13/2018 89
90. Hydrolysis of esters
Hydrolysis of Amide (C-N bond cleavage)
Secondary amide with aliphatic substitution
Procainamide
PABA
4/13/2018 90
91. Hydrolysis of esters
Hydrolysis of Amide (C-N bond cleavage)
Secondary amide with aromatic substitution
Lidocaine
2, 6 Xylidine
N, N-Diethyl
glycine
4/13/2018 91
92. Hydrolysis of esters
Hydrolysis of Amide (C-N bond cleavage)
Tertiary amide
Carbamazepine Iminostilbene
4/13/2018 92