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Metabolism
Terodiline Aromatic p-hydroxylation predominate with R
but benzylic hydroxylation is preferred with S (homework)
ReductionPlay an important role in the metabolism of
compounds containing azo, nitro, and carbonyl
ReductionA- Reduction of aldehyde and ketonesB- Reduction of nitro and azo compounds C- Reduction of sulfones
Azo reductionAr
N
N
Ar
Ar
HN
NH
Ar
ArNH2 +ArNH2
N
HN
SO2
N
N
OH
COOH
N
HN
SO2
NH2H2N
OH
COOH
Nitro reduction
Ar
N
O
O
nitro
Ar-NO
nitroso
Ar
HN
OH
Hydroxylamine
Ar-NH2
N
HN
O2N
O
Cl
Clonazepam
N
HN
H2N
O
Cl
7-amino derivative
Aldehyde and ketones (CO)
R OH
Red.
MinorR-CHO
(O)
MajorRCOOH
main metabolite
R R
O
Red
MajorR R
OH
No reaction
Reduction of sulfoneCH2COOH
S
O
F
Sulindac
CH2COOH
S
F
Sulindac sulfide
ActiveInactive
N.B sometimes Sulphur metabolized to O
O2N
P
OEt
S
OEt
Parathion
Insectcide
O2N
P
OEt
O
OEt
Paroxone
potent acetyl cholinesterase inhibitor
Hydrolytic reactionsA-Esters hydrolysis B- Amide hydrolysis- One of the major biotransformation reactions- Carried out by non specific esterases found in
kidney, liver and intestine (and pseudo choline esterase in plasma)
- Amides undergo hydrolysis by liver microsomal amidases, and esterases.
- Amides hydrolyzed more slowly than esters.
I-Ester hydrolysis
COOH
O
OCOOH
OH
+ CH3COOH
Asprin Salyslic acid
2-Amide hydrolysis
N
OH2N
Carbamazepine
N
HOOC
O
Cl
Indomethacin
Effect of metabolism on therapeutic activityImipramine----desipramine (more
antidepressant)Iproniazid (antidepressant)--------- INH (anti
T.B)
Phase II reactionsGlucuronide conjugationSulphate conjugationAcetylation and acylationGlycine conjugationGlutathion( not all in the liver)
Glucuronide conjugation
Liver enzyme catalyze synthesis of uridene diphosphate glucoronic acid (UDPGA)
It affect OH,SH,COOH,CONHXenobiotic reacts with the activated form of
glucuronic acid (UDPGA) to form highly water soluble conjugate. This reaction is catalysed by microsomal uridine diphosphate glucuranyl transferase(UDPG-transferase).
NHDesipramine
UDPGA
N
O
HOOC
HO
OH
OH
N
N
SH
Methimazole
UDPGA
N
N
S
Glu
NN
H
O
Phenylbutazone
UDPGA
NN
Glu
O
O O
C6H5
C6H5
C6H5
C6H5
(CH2)3CH3 (CH2)3CH3
Sulphate conjugationFor phenols, alcohols and amines.It originates from the body sulfate pole.
Activated by conjugation with ATP to form 3-phosphoadenosine-5-phosphosulfate(PAPS)
Then the sulfate moiety of PAPS bind to OH----------under the effect of sulphotransferase
R-OH R
O
S
OH
O
O
(RSO3H)sulfotransferase
N
N
N
NOO
OH
O
P
HO
OH
O
NH2
PO
OH
O
SO2HO H
PAPS
+
O
HO
Estrone
Phenolsulfotransferase
O
O
S
HO
O
O Estrone sulfate
Acylation reactionsOccur with NH2,OH and SH
NH2
O NH
N
Procainamide
+ CH3COSCoA
Acetyl CoA
Acetyl transferase
NH
O NH
N
O
N-Acetylprocainamide
Although water solubility is not increased ,it helps in terminating the pharmacological activity of the drug or its amino metabolite.
Acetyl transferase is found in many tissues e.g liver
Amino acid conjugationAmino acid glycine and glutamine are most
common.For COOH and aromatic acids Amino acids are not converted to activated
enzymes but COOH is activated with ATP and CoAto form acyl CoA which acylate A.A
OH
O
Phenylacetic acid
ATP PPi AMP
O
CoASH AMP
SCoA
O
Amino acid N-acyltransferase
H2N H
COOH
R
HN
O
R
H
COOH
Amino acid conjugate
Glutathione and mercaptouric acid conjugationGSH is a thiol containing tripeptideIt plays an important role in detoxification(for
electrophilic compounds).(caused by the presence of electron with drowing groups as X,NO2,NO3,epoxide)
It protect vital constituents by its nucleophilic SH gp.
Conjugation is catalyzed by glutathione S-transferase.
Degradation of GSH conjugates ----to mercaptouric acid by microsomal enzymes
R-Br +
HS
HN
NH
O COOH
O
CH(NH2)COOH
Glutathione
Glutathion transferase
RS
HN
NH
O COOH
O
CH(NH2)COOH
1-Glutamyl transpeptidase2-Glycinase
SR
NH2
OHO
Cysteine conjugate
Acylation
SR
HN
OHO
Mercaptouric acid conjugate
O
O2N
Cl
NO2
GSH
Glutathione-S-transferase
O2N
SG
NO2
O
Styrene oxide
GSH
Glutathione-S-transferase
OH
SG
GSH
GS
OH
HN
O
O
N
O
GSH
OH
HN
O
SG
Paracetamol
Glutathion conjugate
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