Phase I Metabolism

General Biotransformation Example of Biotransformation

O O
H2N H 2N
Aliphatic P450 OH P450 OH
R R
Hydroxylation R R
Cl Cl

O
R R
P450 O P450
Epoxidation R R N
R R N
R R H 2N O
H 2N O

O O

Aromatic P450 Cl
H
OH P450 Cl
H
OH
N N
Hydroxylation OH
Cl HO Cl

H 3C
H 3C
R XH N N
R R P450 P450
Dealkylation X H O
R C
R R
H 3C O O OH O
HO OH

H H H
- H
N N OCH3 N N OCH3
FMO/P450 O FMO/P450
-
O
S-Oxidation S + S N O +
S N O
R R S
R R
H 3C H3C

F F
Oxidation

R - -
R FMO/P450 +O F N N FMO/P450 F N N
+ O
N-Oxidation N
N R
R R R OH OH
N CH3 F N CH3 F
N N
N N

HN
HN
ADH/P450 O N ADH N N
Alcohol OH N
R H2N N N
Oxidation R H 2N N N
H
O
OH
H

O O

O O H O HO O
Aldehyde AO/XO/ALDH/P450 ALDH
H 2N P O H 2N P O
Oxidation R H R OH N N

Cl Cl Cl Cl

NH2 O
MAO/P450 R O MAO
Amine R NR2 H
Oxidation H
HO HO

O
N N
O HN N
Imine N R AO/XO/P450 H 2N N N AO
H2N N N
Oxidation R
HN R
R HO
OH HO
OH

CH3 CH3
N N
H3C H 3C

O O
O NTR NTR
+
Nitro Reduction N R H 2N R Cl Cl
-
O NH
N
NH
N
O O
H2NO2S H2NO2S
+
- N NH2
O O

O O

R HN O HN O
GRX/TRX/GSH HS GSH Inotuzumab N
Disulfide S R
Inotuzumab N
NH NH
Reduction R S
Reduction

SH O O
R S HS
S SH
Calicheamicin Calicheamicin

O OH O OH

R OH OH
AZOR H 2N AZOR
Azo Reduction N R N H 2N
R N N NH2
NH2
R HO HO

HO O HO O

O OH O O OH OH
HO HO
OH OH

O CBR OH CBR
Carbonyl
O O OH O NH2 O O OH O NH2
Reduction R R R R
H 3C H 3C
O
O
OH OH
CH3 CH3

O OH
EH EH
Epoxide R OH
Hydration R
R HO
R
O OH
Hydrolysis

O O OCH3 O OH
O CE CE
Ester R OH N N
Hydrolysis R
R O S S
R Cl Cl
HO

O
OCH3
O R OH
OCH3
O
CE
Amide R H3CO N
NH2
H3CO NH2
Hydrolysis R N OH
H

H R OH
R N
various peptidases,
endopeptidases, and proteases
R

Enzymes:
P450 cytochrome P450 GRX glutaredoxin

FMO flavin-containing monooxygenase TRX thioredoxin

ADH alcohol dehydrogenase GSH glutathione (Not an enzyme, the endogenous metabolite
glutathione can chemically reduce disulfide bonds.)
AO aldehyde oxidase
AZOR azoreductase (Not a specific family of enzymes,
XO xanthine oxidase overhead term for enzymes that can reduce azo moieties.)

ALDH aldehyde dehydrogenase CBR carbonyl reductase

MAO monoamine oxidase EH epoxide hydrolase

NTR nitroreductase (Not a specific family of enzymes, CE carboxylesterase

overhead term for enzymes that can reduce nitro moieties.)

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