Lecture 5
Lecture 5
Lecture 5
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
[F eO ] 3+
N N N
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
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
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
N [F eO ] 3+ N N
N N N
N N N N
N N
H H H
6-(methylthio)-purine 6-mercaptopurine
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
N-acetyldapsone
O
H3CO H3CO H3CO
N O xi N N
+
H3CO H2N N NH2 H3CO H2N N NH2 H3CO H2N N NH2
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
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
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
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