Lecture 5

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Oxidative metabolic reactions

 The benzene ring present in drugs when undergo oxidative metabolic reaction is
converted into phenol;
H3C O H3C O

NH [F eO ] 3+ HO NH

O N O O N O
H H
 The electron rich benzene rings are easily oxidized compared to electron
deficient rings, highly substituted rings are not
O
easily oxidized;
H
N
O S
H
N
N
[F eO ] 3+ N Cl
N Cl
CH 2CH 2CH 2N(CH 3)2
Cl
C hlorpromazine

OH
COOH
Cl C l- H
H+
 The presence of electron withdrawing N N
groups on benzene decrease the chances to
NH
undergo oxidative reactions; Cl SO 2N(CH 2CH 2CH 3)2
C lonidine H C l Probenecid

Little oxidation No oxidation


 The aliphatic C=C is oxidized first into epoxides which are converted into diols;
O HO OH

[F eO ] 3+
N N N

O CH3 O CH3 O CH3

Cl Cl
COOH COOH

H2C
O HO O
Alcofenac OH

 some of the epoxides are highly reactive which destroy the cytochrome P-450
activity as they covalently bind with N of the porphyrins;
H2C O
O
H3C H2C NH2
F 3C O CH2
NH
H3C CH3
Fluroxene
H3C O N O
H Allylisopropylacetamide
Secob arbital
N -porphyrin
R R R O R OH R
3+
[F eO ] + R N-porohyrin
R R R R R R
 The benzylic carbon is metabolically oxidized into alcoholic functionality; the
primary hydroxyl is then converted into –COOH group; COOH
CH3 CH 2OH

[F eO ] 3+ [F eO ] 3+

O S O O S O
O S O
HN NH HN NH
HN NH C 4H9
C 4H9 C 4 H9
O O
O
T olbutamide
oral hypog lycemic agent
 The aliphatic side chains undergo two types of oxidation i.e. ω-oxidation at
terminal carbon and ω-1 oxidation at one carbon before terminal carbon;
CH3 CH3 CH3
OH
CH3 COOH CH3 COOH COOH

H3C [F eO ] 3+ H C [F eO ] 3+ H3C
OH 3

 The cyclohexyl undergoes oxidation at carbon 3 and carbon 4; CH3

R R O
R

[FeO ] 3+ [F eO ] 3+

O
OH S O
O
NH
OH The trans 4 metabolite is the major one along with some
NH
minor metabolites A cetohexamide
 Oxidation of carbon hetero-atom system (C-O, C-N and C-S);
i. oxidation at α-carbon results in carbon-hetero atom bond cleavage. The
α-carbon undergoes oxidation only if it possesses H-atoms.
1 1 1
R 3+ R R
[F eO ] 2
R X
2
R X
2
R + R XH

H R OH R O

ii. The second type of oxidative reaction occurs at heteroatom i.e. N-


hydroxylation, N-oxidation and S-oxidation.
 The tertiary amine moiety after oxidation at α-carbon is converted into
secondary amine and secondary amines are converted into primary amines which
then undergo deamination; OH
CH3 CH3
CH3 CH3
[F eO ] 3+ [F eO ] 3+
NH2 O
HN NH2
CH3
M ethamphetam ine

CH3 CH3 OH CH3


NH NH NH
N CH3 [F eO ] 3+ N CH3 NH CH3
O O O
CH3 CH3 CH3 CH3 CH3
Lignocaine
 If α-carbon does not possess H-atom then oxidation reaction at α-carbon is not
possible; Cl
O
Cl
O
[F eO ] 3+
N o further oxidation at alpha carbon
NH H2N

H3C
Ketamine
 The tertiary amides are similarly oxidized into secondary and then primary
amides after oxidation at α-carbon; Cl CH 3

OH N
H3C O
O H O
O N CH3
N N
N
[F eO ] 3+ N O S O
N N
N
Cl HN NH Cl
Cl CH 2CH 2CH 3 F
Cl
O
C hlorpro pamide
F lurazepam
OH

 The ether are converted into alcohols after oxidation at α-carbon;


O O COOH
O
H3CO
HN CH3 HN CH3
HN CH3 CH3
N
[F eO ] 3+
O Cl
OH Indom ethacin
H3C O OH
H3C O
Phenacetin Paracetamo l
 The thioether are similarly metabolized into thiols after oxidation at α-carbon;
CH3
S S OH SH

N [F eO ] 3+ N N
N N N

N N N N
N N
H H H
6-(methylthio)-purine 6-mercaptopurine

H3C CH3 CH 2C6H5


O S
COOH
NH
S
H3C O N S
H CF 3
M ethitural 2-b enzylthio-5-trifluorometh yl
benzoic acid

 Thiopental is converted into pentobarbital by oxidative metabolic reaction, the


C=S is replaced by C=O in this reaction;
H3C CH3
O H3C CH3
O

NH [F eO ] 3+
NH
H3C
H3C
O N S
H O N O
H
T hiopental P entobarbital
 Oxidation at α-carbon in some of the halogenated compounds produced toxic
metabolites which cause hepatotoxicity;
Br Br Cl
[F eO ] 3+ F 3C
F 3C Cl F 3C Cl + H -Br
O
H OH
H aloth ane Trifluoroacetyl chloride acylate the
tissue nucleophile

Cl Cl Cl Cl
[F eO ] 3+
Cl Cl Cl Cl + H -C l
H OH O
C hloroform Phosgene toxic metabolite
OH
OH Cl
NH CHCl 2 OH Cl
Cl NH
NH O
O OH
O 2N HO O
[F eO ] 3+ O O 2N HO
O 2N HO
C hloram phenicol
Toxic metabolite having
oxamoyl moiety.
The presence of water decreased the toxicity of these metabolites by reacting with them, the
–OH of water chemically react with these metabolites to give less toxic products.
Cl Cl HO OH

+ H 2O
O O
The second type of oxidative reaction occurs at heteroatom i.e. N-hydroxylation,
N-oxidation and S-oxidation.
CH3 CH3 CH3 CH3
-H 2 O

NH2 Oxi HN NH Oxi N


OH
HO
O O O O
S S
O O xi O

H3C NH NH2 H3C NH NHOH

N-acetyldapsone
O
H3CO H3CO H3CO
N O xi N N
+
H3CO H2N N NH2 H3CO H2N N NH2 H3CO H2N N NH2

OCH 3 OCH 3 O OCH 3

trimethoprim
O O
O
S
S
S
CH3
N S
N S
N S
CH3
CH3
T he sulfoxide and sulfone
H3C
N metabolites at this S are H3C H3C
also reported. N
N

T hioridazine
Reductive metabolic reactions
Drugs having nitro, diazo or carbonyl group undergo reduction reactions;
The enzymes Aldo-keto reductases are responsible for reduction of the carbonyl
functionality in aldehydes and ketones. These enzymes required a co-factor
NADPH or NADH, these enzymes are present in liver. Oxido-reductases are also
responsible for these reactions;
R R R H R H H
R R

O OH
O OH

Aldehydes are preferably oxidized, very few are reduced;


O OH HO
HO
HO

O O CHO
CH3 O
Cl 3C H Cl 3C H
NH
H NH2
C hloral CH3
Oxi

O xi HO
Propa nolo l HO Red
O COOH
O
Similarly N
OH
chlorpheniramine
is metabolized;
N
H3C CH3

Cl
C hlo rpheniram ine
Drugs having keto group are reduced into chiral alcohols if they are
unsymmetrical, the acetophenone for example is converted into chiral alcohol.;
H+
O OH O
O
CH3 H H
CH3 NH2
NH2
+ +
N
N
R
R O xidized form
R educed form CH3
CH3 HO
O The hydride is shifted
H
from reduced
nicotinamide moiety of
S
O
O
S
O
O the cofactor NADPH to
O
O
NH
NH carbonyl carbon of
NH
NH ketones.
Acetohexam ide S(-)-hydroxyhexam ide

O O HO H
O The preferential formation of
S S one stereoisomer over the other
CH3 CH3
is observed in drug metabolism.
N N This is referred as product
O xisuran
stereoselectivity
Drugs having nitro group are reduced into amine metabolite while diazo
functionality in the drugs first reduced into dihydrazo which upon cleavage
between N-N bond are converted into amines;
H O H O OH
N
N
N NH CHCl2
O 2N CH 3
N N
N O
O 2N HO
O 2N H2N C H 2C H 2 O H
Metronidazole C hloram phenicol

N itrazepam

H2N NH2
NH2 H2N NH2
N
N +
H2NO 2S H2N
H2NO 2S
Prontosil

O COOH The reduction of diazo linkage N=N to


NH S N amines involves intermediate dihydrazo
N O N OH
HN-NH.
Sulfasa lazine
Hydrolytic reactions
 Ester and amide functionalities in the drugs are hydrolyzed metabolically into
more polar metabolites i.e. alcohols, carboxylic acids, phenols and amines. These
polar metabolites are susceptible to phase II reactions.
 Esterases, Amidases, deacylases are the enzymes responsible for hydrolysis of
amide and ester functionalities of the drugs. These enzymes are found in liver,
plasma, kidneys and gastrointestinal tract.
 Hydrolysis is the major biotransformation pathway for drugs having ester
functionality because of the ease of this bioconversion. CH3

COOH
COOH
O
+ C H 3C O O H CH3
O CH3 OH O
OCH 2CH 3
Aspirin
H3C
O
O C lofib rate
O lip id lowering age nt
O
O + OH
H3C H3C OH
H3C N N
N
O OH O OCH 3 NH O
O OCH 3
B enzoylecgonine M ethylecgonine
C ocaine CHCl 2
M a jo r metab olite O 2N O

H3C(H 2C) 14 O
C hloroamphenicol palmitate
Amides are generally more stable than ester and are not easily hydrolyzed compared to
esters;
m o re sin g le bo n d COOH
cha ra cte r m ore do u b le
H3CO
b o nd cha ra cte r
O O CH3
N
R R
R O R N
H O Cl
E ste r A m ide Indomethacin
less electro ne ga tive
m o re e lectro ne ga tive m o re e lectro n
less ele ctro n do na ting CH3
do na tin g NH
Drugs having ester functionality thus easily hydrolyzed into polar N CH3

metabolites and easily excreted from body than drugs having amide CH3
O
CH3
CH3
functionality. O Lignocaine
N CH3 Slow hydrolysis O
NH
OH O
CH3
H2N H3C
H2N N
Procainam ide
CH3 O N O
O
R apid hydrolysis H
N CH3
O H exobarbital

H2N
Procaine
Phase II or Conjugation reactions
 The phase I metabolites having polar functionalities (-OH, -NH 2, -SH, -COOH,
Active –CH2 or -CH) undergo conjugation reactions to become water soluble so
that can easily be excreted from body.
 The conjugating enzymes are responsible for the formation of these conjugates
like glucoronic acid conjugates, sulfate conjugates, amino acid conjugates,
Glutathione conjugates.
 Methylation and acetylation also occurs to terminate the activity of drugs though
they yield less water soluble metabolites. OH
NH O
COOH COOH
O R-XH RX O Cl 3C CH 2-OH
OH OH CHCl 2
OH OH trichloroethanol O 2N OH
HO UDP-G lucuronyl HO
transferase
O-UDP
β-glucuronide C hloroamphenicol
Uridine-5’- COOH
diphospho-α-D-
NH CH3
glucuronic acid R
O
X is any polar functionalities (-OH, -NH2, -SH, H5C 6 C6 H5
HO
P aracetamol
-COOH, Active –CH2 or -CH). N N

O O
H R

Formation of C-glucuronide
 The sulfate conjugates occurs primarily with phenols and occasionally with
alcohols, aromatic amines, and N-hydroxy compounds.
 The enzyme sulfotransferases found in liver, intestine, kidneys are responsible
for the formation of sulfate conjugates.
-
O
O XR
S O
O O Adenine R-XH -
O S O
O P O sulfotransferase O
HO transferase
H2PO3O OH OH
3'-phosphoadenosine-5'-phospho HO
sulfate CH3
HN CH3
NH CH3 HN O
CH3
OH CH3
O T erbutaline
HO
P aracetamol
-
OH
OSO 3
OH -
OSO 3 HO
N CH3
N CH3 HN CH3
HO
O CH3
HO O CH3
HO S albutam ol

Both these sulfate conjugates of paracetamol are reported.


 The amino acid conjugates are formed by reacting the –COOH of the Phase I
metabolites with glycine and glutamine and some other amino acids.
 In contrast to glucuronic acid and sulfate, glycine and glutamine are not
converted into activated coenzymes. Instead the carboxylic group of the substrates
is activated with ATP and Co-enzyme A (CoA) to form a n acyl-CoA complex
which then acylate the amino acids in the presence of N-acyltransferase enzymes.
OH AMP SCoA
A TP

O O O
R R R

G lycine or glutamine
N -transferase
O

R OH
NH
R
O NH2
R O
HO
amio acid conjugate

 The glutathione conjugates are formed by reacting the –SH group of glutathione
with electrophilic center of the Phase I metabolites. The conjugates then
hydrolyzed releasing different amino acids to smaller polar water soluble products.
O COOH

NH
HOOC NH NH2

O
HS
G lutathione
O COOH O COOH
G lutathione
NH NH
HOOC NH NH2 S -transferase HOOC NH NH2
E +
O O
electrophilic
HS E S
substrate
G lutathione G lutathione
A dduct
O
O O
CH3
NH2
NH HO NH2
HO HOOC NH
O
E S
E S M ercapturic acid E S
derivative

Formation of glutathione conjugates and their conversion to mercapturic acids

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