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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.).
e.g. Saccharin NH
41
Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in
( 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
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%
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
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
* 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 )
epoxide OH
Epoxide
Cyto-P450 Hydrase
Trans-diol
C C C C C C
Epoxidation
O
OH
Examples:
(1) Carbamazepine
O OH OH
(2)
Epoxidation
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
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
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).
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
O
OH
H Deamination
Hydroxylation
Drug C H + NH3
Drug C- NH2 Drug - C-NH2
of -carbon
Carbinolamine
( unstable )
Examples:
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
47
Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in
N Cl
CH3
CH2-CH2-CH2-N
CH3
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
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
N N
CH3 H
Pethidine
oxidation H3C N
Ph
OH
H3C N
H
Phenmetrazine - C oxidation
Ph
Lactam
H3C N O
H
e.g. 1 : Amphetamine
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
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
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.
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
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 )
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 )
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
e.g.
Alcohol Aldehyde
CH3-OH dehydrogenase CH2O dehydrogenase HCOOH
Methanol Formaldehyde Formic acid
By ethanol
as antidote Toxic for optic nerve
= blindness
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 )
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
e.g.1 : Metronidazole
O2N CH3
Nitro-reductase H2 N CH3
N N
CH2-CH2-OH CH2-CH2-OH
Metronidazole
e.g 2 : Chloramphenicol
H H
Azo-reductase R-NH2 H2N - R'
R-N = N - R' R- N - N - R' +
Azo comp. Hydrazo deriv.
1 ry Amines
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
acetic acid
Salicylic acid
Esterase
H2N COO-CH2-CH2-N H2N COOH + HO-CH2-CH2-N
Amidase
H2N CO-NH-CH2-CH2-N H2N COOH + H2N-CH2-CH2-N
Procainamide PABA
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
Paracetamol
Phenacetin
( Active )
( Prodrug )
O CH2-CH3 O CH2-CH3
NH-CO-CH3 NH2
Phenacetin Phenetidine
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
Conjugation Reactions:
( I ) Glucouronic acid formation (glucouronidation)
COOH COOH
ZH
O Glucourinyl O
+ R-ZH OH
OH
transferase + UDP
OH OUDP OH
OH OH
The formed ( glucouronides are highly ionizalole , polar & rapidly excreted
Gurpreet Singh
M.Pharmacy(Pharmaceutics)
Guru Nanak Dev University
e-mail. surtall3@yahoo.co.in
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
OH O-SO3H
PAPS
e.g. Sulfotransferase
NH-COCH3 NH-COCH3
Paracetamol
+ 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
e. g. 1: Salicylic acid
*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
COOH CO-NH-CH2-COOH
glycine
+ NH2-CH2-COOH
Benzoic acid
Hippuric acid
Thiol R - SH R - S-CH3
* It does not the water solubility of the product but it terminates the effect of compound.
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 )
(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 )
O NH2
Cysteine Glutamine
NH-C-CH2-CH2-CH-COOH
HS-CH2-C
Glutathione
CO-NH-CH2-CH2-COOH Glycine
Nu: thiol
essential
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
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
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
R R
Glutathione
O
OH
Epoxide
65