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Gurpreet Singh

M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in

DRUG BIOTRANSFORMATION
( Metabolism )
Any small organic comound or toxins or food in the body is metabolized
(xenobiotics + endogerous subst.).

0 Xenobiotics: Any foreign substance that enter the body.


** Metabolism converts the substance into more polar unit that can be easily
eliminated through normal processes of excretion kidney, saliva,
sweat. etc.

* Substances resisting metabolism:

(1) Highly lipophilic substances., cannot be transported by body


fluids to reach the site of metabolism so they are stored in fatty
tissues.
e.g. Insecticide they are polyhalogenated compound & resist metabolism.

Polychlorinated biphenyl comp.


Cl Cl

(2) Highly hydrophilic & ionized species as enzymes in liver are


surrounded with fatty tissues so hydrophilic & ionized drugs cannot
reach the enzyme. O
S
O

e.g. Saccharin NH

(3)Water insoluble compounds (mineral oil, Basic salts) cannot be


biotransformed in body fluid.

Pase II ( Conjugation) METABOLISM Pase I ( Chemical change)

41
Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in

Phase ( I ) metabolism =( functionalization reaction)

Phase I metabolism leads to introduction or demasking of a functional gp.


to give polar metabolite which then undergoes phase II reaction.

1 Reactions involved in phase I :


(1) Oxidation. (2) Reduction. (3) Hydrolysis.

( I ) Oxidation
Enzymes involved in oxidation
(1) Microsomal enzyme system. ( non specific enzyme )
Its found in Cytochrome oxidase = Cyt P-450 : & consists of Hemoprotein
( Cyt - Fe++ - Co ) with absorption band = 450 nm

Fe++ CO
Hemoprotein Fe+++ Hemoprotein Cyto 450
Complex

So its monocarbonyl derivative essential for oxidation of many substances.


(2) Non microsomal enzyme system. ( specific enzyme )
Its outside the liver e.g. alcohol dehydrogenase & aldoreductase
(3) NADPH (= Cytochrome P 450 reductase enzyme )

Oxidation Reactions
(B) ** Oxidation of Aromatic moieties ( Aromatic Hydroxylation )

(1) Any drug containing phenyl ring will undergo aromatic Orth & para. hydroxylation
) ,This occurs to give phenols through the formation of epoxide intermediate.
Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in
R
R R R
Spontaneous OH
Mono-oxidase rearrangement
+
( hydroxylation )
Arene O OH
Arene epoxide Major Minor
( highly toxic intermediate ) P-hydroxy deriv. O -hydroxy deriv.
90% 10%

** Hydroxylation occur mainly in P position which is the least hindered site.

** Mechanism & Possibilities of arene oxidation

Spontaneous
rearrangement
P-hydroxy deriv.

OH

R R
epoxide
R R hydrase
Catechol
+ H2O OH OH
Mono-oxidase OH OH

G-SH
Arene O Phase II metabolism
Arene epoxide OH

(highly toxic) SG
R
Nitro gp.
metabolism
{ Toxic ,Carcinogenic
OH
metabolite }
NO2

(2) The arenol formation depends on the type of Substituents on aromatic ring
* If R gp.is Electron donating group as CH3 or NH2 Hydroxylation is Spontaneous

e.g.1 : Amphetamine

CH2-CH-NH2 rapid P-hydroxylation HO CH2-CH-NH2


CH3 CH3
electron donating gp.

43
Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in

e.g.2 Phenobarbital

electron
donating O H O H
gp. N N
Et Et
O O
P - Hydroxylation
N N
O H O H
HO

Phenobarbital P - hydroxy deriv.

* If R gp.is ele Electron withdrawing group as -CO , NO2 , C=N or SO2 gps
i.e. ( = deactivated ring ) so these compounds resist metabolism & have long t1/2
e.g.
COOH
Cl
H
Cl H N
O Cl
N
Cl O Cl N
H
Cl
SO2NHC3H7
TCDD
( toxic pollutant ) Clonidine
Probenicid ( antihypertensive )

Resists metabolism
due to presence of electron withdrawing gps.

So in drug with more than one aromatic ring , the more electron rich ring (with electron
donating gp.) is only hydroxylated

* e.g. : Valium CH 3 CH 3
O O
N N
Metabolic oxid.

Cl N N
Cl
electron rich

Valium OH
Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in

(3) If the two aromatic rings are identical only one is hydroxylated

OH
N N N N
Oxidation
O O O O

H C4H9 H C4H9

Phenylbutazone
( anti-inflammatory )

** Olefinic oxidation: (Non aromatic double bond oxidation).

epoxide OH
Epoxide
Cyto-P450 Hydrase
Trans-diol
C C C C C C
Epoxidation
O
OH

Examples:
(1) Carbamazepine
O OH OH

Epoxide Hydrase 10,11-transdiol


( inactive metabolite )
N Epoxidation
N N
O NH2
O NH2 O NH2
Carbamazepine
10,11-epoxide
( active metabolite )

(2)

Epoxidation

(3) stilbene CH3

H HO H
Oxidation H

H OH
H H
O
Stilbene
45
Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in

* Toxicity from Olefinic compounds

O O N
O
N
O + Guanidine

O O Electrophilic
O O O-CH3 HO O O
attack
2,3-epoxide Nucleophilic adduct
Aflatoxin ( Natural product )
N7_ guanyl covalent

Cancer
( C ) Oxidation involving carbon-Heteratom system

I} (Oxidations involving N C system):


Three metabolic pathways may occur

(1) N- oxidative dealkylation

OH
O
H Hydroxylation
H
Drug N- C
Drug N- C Drug NH2
+ HC
of -carbon

Carbinolamine
( unstable )

* This should occurs if amino gp. bears small alkyl gp having -carbon
with H-atom ,
e.g. : Me , Et, isopropyl ., but not occurs if R = t-butyl

** oxidative dealkylation occurs due to lack of (H) attached to carbon adjacent to (N).

(2) N- Oxide formation or Hydroxylamine formation or


N- Nitroso formation

CH3
CH3 N- Oxide
Drug N Drug N O
CH3 formation
CH3
N- Oxide
Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in

Drug N
(3) H
Drug N Drug N O
OH

Hydroxylamine deriv. N-Nitroso deriv.

Oxidative deamination : only if carbon adjacent to nitogen carrys H-atom

O
OH
H Deamination
Hydroxylation
Drug C H + NH3
Drug C- NH2 Drug - C-NH2
of -carbon
Carbinolamine
( unstable )

Examples:

(A) 3ry Aliphatic & alicyclic compounds amines

e.g. (1) Imipiramine

N-dealkylation
N
Small gp.
+ CH2O
CH3 N
CH2-CH2-CH2-N H
CH3 CH2-CH2-CH2-N
CH3
Imipiramine
Despiramine
( acive metabolite )

N-dealkylation

Inacive metabolite
+ CH2O
N
H
CH2-CH2-CH2-N
H

N.B. : Metabolism of 3ory amine to 2ory is rapid process


While metabolism of 2ory amine to 1ory is Slow process

47
Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in

e.g . (2) Chloropromazine ( CPZ )


S
N- dealkylation

N Cl
CH3
CH2-CH2-CH2-N
CH3

e.g. (3) Benzmethamphetamine

CH3 CH3
CH2 CH2
CH2 CH N CH2 CH N
CH3 N-dealkylation H

+CH2O
Methmphetamine deriv.
N-dealkylation

CH3
H
CH2 CH N + CHO
H

Amphetamine

( B ) 3ry Alicyclic amines


e.g.1 : Nicotine
Lactam formation
Pathway
N OH
Oxid. N O Lactam
- carbon N CH3
hydrxylation N CH3
N
OR
N CH3 N

Nicotine N-dealkylation H
OR N

N
Aromatic
N-oxidation N CH3

O
Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in

e.g.2 : Pethidine Ph COOEt Ph COOEt


N- dealkylation

N N

CH3 H

Pethidine

( C ) 2ry alicyclic amines Ph

oxidation H3C N
Ph
OH

H3C N
H
Phenmetrazine - C oxidation
Ph
Lactam
H3C N O
H

( D ) 1ry aliphatic amines

Undergo Oxidative deamination if - cabon bearing H-atom

e.g. 1 : Amphetamine

CH3 CH3 CH3


H -carbon deamination
H +
CH2 CH N CH2 C N CH2 C NH3
H Hydroxylation
H
\ O
Amphetamine O--H

Carbonolamine Phenyl acetone


( unstable )

e.g. 2 : Serotonin

HO CH2-CH2-NH2 HO CH2-CHO
MAO + NH3
N N
Monoamine oxidase
H H

Serotonin

49
Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in

e.g. 3 : Norepinephrine

HO CH-CH2-NH2 CH-CHO
MAO HO
OH OH
HO Monoamine oxidase HO
+ NH3

NE

N-deamination MAO
Epinephrine
NE Aldehyde + Ammonia
Monoamine oxidase

In absence of - cabon bearing H-atom , No deamination occur & only N


Hydroylation occurs followed by N-Nitroso derivative formation

e.g. Homologue Of amphetamine ( phenteramine )


CH3
CH3 CH3 Further
N-Hydroxylation oxidation CH2 C N =O
CH2 NH2 CH2 C NH O-H
C
CH3
CH3 CH3
Nitroso metabolite
Hydroxylamine deriv.
Further
oxidation

CH3
+ O
CH2 C N
O
CH3

Nitro derivative
( E) 2ry aliphatic amines
e.g. Methamphetamine
CH3
H
N-dealkylation N
CH2 CH
CH3
H
CH3
CH2 CH N
H OR Amphetamine Major
Methmphetamine
CH3
CH3
Hydroxylamine
formation CH2 CH N
OH

Hydroxylamine derivative Minor


Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in

( F ) Aromatic amines (1ry, 2ry , 3ry aromatic amines)


H H
H CH3 H H N
N N Oxidative
Oxidative
dealkylation
dealkylation
H CH3
CH3 CH3 N
1ry amine
N 2ry amine 1ry amine

OR OR
O
CH3 CH3
2ry amine HO CH3
3ry amine N N

N-Oxidation N- Hydroxylation

1ry armatic amine s are metabolized either by minor phase I N-nitroso & finally nitro
Formation, not by Oxidative deamination

H H H OH NO2
N=O
N N- Hydroxylation N Oxid. Oxid.

1ry amine Hydroxylamine Nitroso deriv Nitro deriv


deriv

II} (Oxidations involving C S system)

H OH O
Cyt.P450
R S C R S C R-SH + C

Unstable hemithioacetal
or hemithioketal

e.g. 1 S
S
Suloxidation
N S-CH3 Sulfoxide deriv. (inactive)
N S-CH3
CH2-CH2-CH2-N(CH3)2
CH2-CH2-CH2-N(CH3)2

S
S O
S-OXid. O
Further N S - CH3
side chain N S - CH3
O
Suloxidation
CH2-CH2-CH2-N(CH3)2
CH2-CH2-CH2-N(CH3)2

Sulfone deriv.( Active )


Sulfoxide deriv.( Inctive )
51
Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in

S H
CH3
e.g. 2 S
N
N
N 1) -C Hydroxylation
N
N N + H-CHO
2) S-dealkylation
N N
H
H 6-Mercaptopurine
6-Methy- thiopurine ( Anticancer )
( Anticancer )

** Or They undergo Oxidative desulphonation

Thione
C S C O ketone
= thioketone

e.g. Thiopental

O O
Et NH Et NH
Oxidative
S O
desulphonation
NH NH
O O

Thiopental Pentobarbital
( general anaesthetic ) ( Sedative & hypnotic )

III} (Oxidations involving C O system)

H OH O
Cyt.P450
R O C R O C R-OH + C

Unstable hemiacetal
or hemiketal

e.g. O CH2-CH3 O H
O-dealkylation O

- CH2-CH3 + H-C-CH3

Acetaldehyde
NH-CO-CH3 NH-CO-CH3
Phenetidine Paracetamol
( Prodrug )
Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in

** If compound contains more than one ether linkage ,Only one undergoes

O-dealkylation

NH 2 OCH 3
OH
N Regioselective
H 2N CH2 O-CH3 OCH 3 + CH2O
N metabolism
OCH 3 OCH 3

Trimethoprim

** this is an example of Regioselective metabolism of the least hindered gp.

Non-Microsomal Oxidation Reactions

(1) Oxidation of Alcohols & Aldehydes


Alcohol
R-CH2-OH dehydrogenase RCHO
10ry alc. Aldehyde

e.g.
Alcohol Aldehyde
CH3-OH dehydrogenase CH2O dehydrogenase HCOOH
Methanol Formaldehyde Formic acid

By ethanol
as antidote Toxic for optic nerve
= blindness

* So ethanol is used as antidote of methanol as it competes with the alc.


dehydrogenase enzyme & prevents oxidation of CH3OH to HCHO

OH O
Alcohol
R-CH-R dehydrogenase
R - C -R
20ry alc. Ketone

53
Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in

(2)Oxidative dehalogenation

Cl Cl Cl OH
MO. - HBr
CF3 - C - H CF3 - C -O H CF3 -C = O CF3 -C = O
Br Br Trifluoromethyl Trifluoroacetic
acetyl chloride acid
Halothan
( causes liver necrosis on long run )

Non-Microsomal Metabolic Reduction

(1) Reduction of Carbonyl groups


(a) Aldehyde Oxidation R-COOH ( Major )

R-CHO
Reduction R-CH2-OH ( Minor)

e.g. Chloralhydrate

OH - H2O Aldo-reductase
CCl3-C-H CCl3-CHO CCl3-CH2-OH
OH
Chloral Trichloro ethanol;
Chloralhydrate (aldehyde ) ( sedative &hypnotic )

(b) Ketone
HO H OH
O H
Keto-reductase R- C- R
R- C- R R- C- R +
Ketone S (isomer) R (isomer)

e.g. Amphetamine
HO H
Keto reductase CH2 C CH3
S(-)
CH3 CH3 = major 75%
Oxidative
CH2 CH NH2 CH2 C Or
deamination
O
Phenyl acetone H OH
Amphetamine
CH2 C CH3
Keto reductase
R( +)
= Minor 25%
Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in

So this Ketone reduction confirms the stereo selectivity Ketoreductase


enzyme

(2) Reduction of Nitro compounds

R-NO2 R-NO R-NH-OH R-NH2


Nitro Nitroso Hydroxylamine Amine

e.g.1 : Metronidazole

O2N CH3
Nitro-reductase H2 N CH3
N N
CH2-CH2-OH CH2-CH2-OH

Metronidazole

e.g 2 : Chloramphenicol

(3) Reduction of Azo compounds

H H
Azo-reductase R-NH2 H2N - R'
R-N = N - R' R- N - N - R' +
Azo comp. Hydrazo deriv.
1 ry Amines

e.g. Sulphasalazine (prodrug )

N
NH-SO2 Azo-reductase N
N=N OH
NH-SO2 NH2
H2 N OH
( from intestinal flora)
COOH
Salphasalazine COOH
Salphapyridine
p-aminosalicylic acid

55
Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in

Non-Microsomal Metabolic Hydrolysis

(1) Hydrolysis of Esters: By esterase enzyme


e.g. (1) As pirin (acetyl salicylic acid )
COOH O
COOH O
O-C-CH3
Esterase OH
+ H O-C-CH3

acetic acid
Salicylic acid

e.g. (2) Procaine (local anaesthetic )

Esterase
H2N COO-CH2-CH2-N H2N COOH + HO-CH2-CH2-N

Procaine PABA TEA

(2) Hydrolysis of Amides: By amidase enzyme :

(advantage.) : Slowly hydrolyzed than esters into acid + amines

Amidase
H2N CO-NH-CH2-CH2-N H2N COOH + H2N-CH2-CH2-N

Procainamide PABA

** So procainamide of longer duration than procaine


Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in

Conclusion
Effects of metabolic biotransformation on the pharmacological activity of drugs:
(1) Metabolic inactivation: O
O
S
(Most of drugs) OH O
OH

e.g. PAPS

Phenol Phenyl hydrogen sulphate


( Inactive, as it is very water
soluble, readily excreted )

(2) Bioactivation: O CH2-CH3 O H


O-dealkylation
(Formation of active metabolites).
- CH2-CH3
NH-CO-CH3 NH-CO-CH3

Paracetamol
Phenacetin
( Active )
( Prodrug )

(3) Intoxication: (Formation of toxic metabolites).


e.g.Deacetylation of Phenacetin to p-Phenetidine lead to METHAEMOGLOBINAEMIA

O CH2-CH3 O CH2-CH3

Deacetylation Responsible for


Methaemoglobinaemia

NH-CO-CH3 NH2

Phenacetin Phenetidine

(4) Alternation of pharmacological effect CH3 CONH-NH2


CONH-NH-CH
i.e. Metabolite with a Dissimilar activity CH3

N-Dealkylation
N
N

Iproniazide INH
(antidepressant) ( Anti T.B.)

57
Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in

Phase ( II ) metabolism =( Conjugation)


Conjugation
Aim of phase II : Conversion of metabolite of phase I to more polar structure
* Phase II = the conjugation reactions achieved by family of enzymes called transferases
* The conjugated products are highly hydrophilic & ionized to be readily excreted.

D ( phase I) + C.DC (conjugated products)


hydrophilic water soluble
&
inactive excreted

Conjugation Reactions:
( I ) Glucouronic acid formation (glucouronidation)

- It is most common pathway in phase II due to availability of D-glucouronic


acid.
* Donor : uridine diphospho-glucouronic acid ( UDPGA ) COOH

*Acceptor : R-ZH { Z = O (alcohol or phenol ), O


OH
N ( amine ) ,
OH OUDP
S ( thiol) , OH

C (acidic) , COOH } Active form of Donor

* Enzyme transferase : Glucouronyl transferase

COOH COOH
ZH
O Glucourinyl O
+ R-ZH OH

OH
transferase + UDP
OH OUDP OH
OH OH

* Z= O ( alc. or phenol ) , N (amine ) , S ( thiol ) , C , COOH

The formed ( glucouronides are highly ionizalole , polar & rapidly excreted
Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in

Examples : (1) Salicylic acid


COOH

O OO-C
OH
COOH UDPGA OH
GT OH Ester glucouronide
OH OH

COOH COOH
Salicylic acid UDPGA
O O
GT OH
Ether glucouronide

OH
OH

(2) Mercaptopurine
COOH
SH S S-C6H9O6
H O
H H
N N UDPGA OH N N N N

GT OR
N N OH
N N N N
OH

Mercaptopurine

(3) Phenylbutazone

N N N N
UDPGA
Phenylbutazone O O HOOC O O
GT
( anti-inflammatory ) C4H9
H C4H9 O
OH

Activated carbon
by 2 C=O gps OH
OH

Advantages of glucouronidation
(1) Common pathway due to available supply of Dglucose which is converted to
UDPGA
(2) Many functional gps are attached to UDPGA

59
Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in

( II ) Sulphate Conjugation : ( not common )


It is a limited pathway due to low supply of sulphate conezyme.

* Donor: Active Sulphate = PAPS ( 5\- phosphadenosine-3\ - phosphosulphate ).


* Acceptor: Phenols, alcohols, N-hydroxyl amines.
* Enzyme transferase : Sulfotransferase
O
Sulfotransferase
R-OH + PAPS
R - O S OH + PAP
O

OH O-SO3H
PAPS
e.g. Sulfotransferase

NH-COCH3 NH-COCH3

Paracetamol

( III ) Acetyl Conjugation


* Acetylation process doesnot increase the hydrophilicity of the compound
but it terminates the biologicall activity.

* Donor : Acetyl CO A = ( CH3COSCOA).


* Acceptor : 1ry amines (aliphatic or aromatic ) , Hydrazines , Sulphonamides & hydrazides.
* Enzyme transferase : Acetyl transferase ( AT )

+ acetic acid
* Examples:
(1) amines AT
R-NH2 + CH3CO-SCoA R-NHCO-CH3 + HSCoA

AT
(2) Hydrazine R-NH-NH2 R-NH-NH-CO-CH3
Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in
CO-NH-NH2
CO-NH-NH-CO-CH3
AT
(3) Hydrazide INH
N
N

NH2
(4) Sulphonamides NH-CO-CH3
AT
* Crystal urea = Inactive &
less soluble
SO2-NH-R
SO2-NH-R

(5) Procaine & Procainamide

( IV ) Glycine & glutamine conjugation :

* Donor : Glycine or glutamine ( non-actived endogenous amines )


* Acceptor : Aromatic carboxylic acids , aryl & alkyl carboxylic acids
in form of active acetyl CO-A.
* Enzymes : Acyl transferase

* Steps of Glycine cobnjugation


glycine
Kinase + NH2-CH2-COOH
Acyl-transferase R-CO-SCOA R-CO-NH-CH2-COOH
R-COOH + ATP R-CO-AMP
Acyl-transferase
HSCoA Active form Amide
Acyl-adenosine
monophosphate of acceptor

e. g. 1: Salicylic acid

COOH CO-SCoA glycine CO-NH-CH2-COOH


Phase II + NH2-CH2-COOH
OH OH OH
activation Acyl-transferase

Salicylic acid Active form Salicyluric acid


of acceptor

*N.B. Glycine is common for human & Glutamine is common for birds

61
Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in

e.g. 2 : Benzoic acid

COOH CO-NH-CH2-COOH
glycine
+ NH2-CH2-COOH

Benzoic acid
Hippuric acid

( V ) Metabolic methylation (methyl conjugation) = O- , N- & S-methylation.

* Donor: SAM (5- adenosyl methionine).


*Acceptor: R (Ar) - OH R (Ar)- O-CH3
Alcohol or phenol

Amine R - NH2 R - NH-CH3

Thiol R - SH R - S-CH3

More polar Less polar but inactive

* It does not the water solubility of the product but it terminates the effect of compound.

Examples : (1) Epinephrine

HO CH-CH2-NH2 CH-CH2-NH-CH3
HO
SAM
OH OH SAM & COMT CH3-O CH-CH2-NH-CH3
HO N-Methyl transferase HO OH
Regioselective metabolism HO
NE Epinephrine ( for OH at position 3 not 4 )
( active neurotransmitter )

( Inactive Metabolite )

N.B. This is an example of REGIOSELECTIVE METABOLISM foe


position 3 methylation & not for position 4 of catechol gp. by
COMT
Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in

(2 ) Smethylution:
S CH3
S H
N
N
N
N SAM
N N
N N S-metyl transferase
H
H
6-Methy- thiopurine
6-Mercaptopurine ( Activer )

( VI ) Glutathione conjugation = ( Mercaptouric acid formation ):


( the most important pathway)

It is an important detoxifying pathway as the glutathione (GSH) moiety


contain Nucleophilic gp = ( SH gp) reacts with toxic electrophilic
species & prevents their effect on cellular constituents.

So this pathway is important for prevention of liver necrosis & cancer


from electrophilic drugs by their detoxification & elimination

* Donor : Glutathione tripeptide = Cysteine + glutamine + glycine


( activated inside the body )

O NH2
Cysteine Glutamine
NH-C-CH2-CH2-CH-COOH

HS-CH2-C
Glutathione
CO-NH-CH2-CH2-COOH Glycine
Nu: thiol
essential

* Acceptor : Electrophilic species ( electron deffecient )

63
Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in
e.g. Alkyl or aryl- halide , Epoxide , Chlorinated nitro compound ,
Organic nitrate & Conjugated enone

R R
NO2
O
Cl H 2C C C R
Cl
H
Cl Electrophilic Glutathione
O
Alkyl or Chlorinated Conjugated OH
aryl halide nitro comp. enone Epoxide

* Enzyme transferase : Glutathione S- transferase


*Scheme of biosynthesis of mercapturic acid.

O NH2
O NH2
NH-C-CH2-CH2-CH-COOH
leaving
NH-C-CH2-CH2-CH-COOH
E -S-CH2-CH
Glutathione
E+ + HS-CH2-CH
-S - transferase CO-NH-CH2-CH2-COOH
CO-NH-CH2-CH2-COOH
Electrophile GSH adduct ( large complex )
= acceptor Glutathione ( G-SH )
= donor
(1) - glutamyl transpeptidase

(2) glycinase

O NH2
NH-C-CH3
N-Acetylation E -S-CH2-CH
E -S-CH2-CH CH3-CO-CoA COOH
COOH ( Acetyl transferase )
S -substituted cysteine
( premercaptouric acid deriv.)
( Mercaptouric acid deriv.)
N-Acetyl-cysteine derivative

e.g. Chlorinated nitro compounds

NH2 NH-CO-CH3
Cl -S-CH2-CH -S-CH2-CH
1- GSH / GST COOH
Cl NO2 N-Acetylation COOH
Cl NO2 Cl NO2
2- - glutamyltranspeptidase CH3-CO-CoA
3- glycinase
( Acetyl transferase )
S -substituted cysteine
( premercaptouric acid deriv.) ( Mercaptouric acid deriv.)
Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in

Q- Carry out possible metabolic pathway for the following epoxide ?

R R

Glutathione
O
OH
Epoxide

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