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