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Metabolism final

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Page 1: Metabolism final

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Definition of Metabolism

Metabolism is defined as the sum total of all chemical reactions that occur in the body.

In Other WordsMetabolism of drugs is defined as the

conversion from one chemical form to another.

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Converting lipophilic to water soluble compounds

Xenobiotic

Reactive intermediate

Conjugate

Phase I - Activation

Phase II - Conjugation

Excretion

Lipophilic

(non-polar)

Water soluble(polar)

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ORGAN SITES OF DRUG METABOLISM

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Organ Sites of Drug Metabolism

• Liver

• Small intestine

• Kidney

• Skin

• Lungs

• Plasma

• All organs of the body

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CELLULAR SITES OF DRUG METABOLISM

CELLULAR SITES OF DRUG METABOLISM

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Cellular Sites Of Drug Metabolism

• Cytosol

• Mitochondria

• Lysosomes

• Smooth endoplasmic reticulum (microsomes)

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Drug metabolising enzymes

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The enzymes are broadly divided into two categories

Microsomal

Non Microsomal

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Hepatic microsomal enzymes (oxidation, conjugation)

Extrahepatic microsomal enzymesExtrahepatic microsomal enzymes (oxidation, conjugation)(oxidation, conjugation)

Hepatic non-microsomal enzymesHepatic non-microsomal enzymes (acetylation, sulfation,GSH, (acetylation, sulfation,GSH, alcohol/aldehyde dehydrogenase,alcohol/aldehyde dehydrogenase,hydrolysis, ox/red)hydrolysis, ox/red)

Drug Metabolism

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PATTERNS OF DRUG METABOLISM

1. PARENT MOLECULE PHASE 1 METABOLISM METABOLITE

2. PHASE 1 METABOLITE PHASE 2 METABOLISM METABOLITE

3. PARENT MOLECULE PHASE 2 METABOLISM METABOLITE

4. PHASE 2 METABOLITE PHASE 1 METABOLISM METABOLITE

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PHASES OF DRUG METABOLISMPHASES OF DRUG METABOLISM

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Phase I Metabolism

R ROH R RCOOH

R RSH R RNH2

Polar groups are exposed on or introduced to a molecule

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Phase I Reactions

OXIDATION

REDUCTION

HYDROLYSIS

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Oxidative Reactions

1. Oxidation Of Aromatic Carbon Atoms

acetanilide p-hydroxyacetanilide

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2.Oxidation of olefins(C=C bond)

Carbamazepine Carbamazepine-10,11-epoxide

Trans-10,11-dihydroxy carbamazepine

H2OH2O

Epoxidehydrase

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3.Oxidation of Benzylic Carbon Atom

Tolbutamide Primary Carbinol Corresponding aldehyde

CorrespondingCarboxylic acid

2OH

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4.Oxidation of Allylic Carbon Atoms

Hexobarbital3-hydroxy Hexobarbital

Allylic Carbon Atom

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5.Oxidation of Carbon Atoms Alpha to Carbonyls and imines

OH

Diazepam3-Hydroxy diazepam

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6.Oxidation of Aliphatic Carbon Atoms

5-Hydroxy Valproic Acid(minor product)

4-Hydroxy ValproicAcid(major product)

OH

HO

ω -Oxidation

ω-1 Oxidation

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7.Oxidation of Alicyclic Carbon Atoms

OH

Minoxidil 4’-Hydroxy minoxidil

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8.Oxidation of carbon-heteroatom systems

A.Carbon-Nitrogen systemsi. N-Dealkylationii. Oxidative Deaminationiii. N-Oxide Formationiv. N-Hydroxylation

B.Carbon-Sulfur Systems

i. S-Dealkylationii. Desulfurationiii. S-Oxidation

C.Carbon-Oxygen Systems

i. O-Dealkylation

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A.Carbon-Nitrogen systems

i. N-Dealkylation

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ii. Oxidative Deamination

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iii. N-Oxide Formation

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iv. N-Hydroxylation

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B.Carbon-Sulfur Systems

i. S-Dealkylation

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ii. Desulfuration

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iii. S-Oxidation

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C.Carbon-Oxygen Systems

i. O-Dealkylation

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9.Oxidation of Alcohol,Carbonyl and Carboxylic Acid.

AlcoholDehydrogenase

Aldehyde Dehydrogenase

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Reductive Reactions

1. Reduction of Carbonyls (Aldehyde and Ketones)

H2O

Aldehyde

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Ketones

MethadoneMethadol

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2.Reduction of Nitro Compounds

R N O 2 R N H 2

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3.Reduction of Azo Compounds

R N = N R ' R N H 2 + R ' N H 2

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Hydrolytic Reactions1.Ester Hydrolysis

R C O O R ' R C O O H + R ' O H

Enalaprit

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2.Amide Hydrolysis

R C O N R ' R " R C O O H + H N R ' R "

+ NH2CH2CH2N(C2H5)2

Procainamide

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CarbamazepineIminostilbine

H

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3.EPOXIDE HYDROLASE

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PHASE II METABOLIC PATHWAYS

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D+ ENDOX DX+ENDO

PHASE 2 METABOLISM

A molecule endogenous to the body donates a portion of itself to the foreign molecule

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PHASE II REACTIONS Glucuronidation

Sulfate Conjugation

Acetylation

Glycine Conjugation

Methylation

Transulfuration

Glutathione Conjugation

Mercapturic Acid Synthesis

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GLUCURONIDATION

Uridine-5’diphospho--D-glucuronic Acid

The microsomal enzyme glucuronyl transferase conducts the donation of glucuronic acid from the endogenously synthesized UDPGA to various substrates to form glucuronide conjugates. Examples of such substrates are morphine and acetaminophen.

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SYNTHESIS OF UDPGA

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Glucuronidation of Benzoic Acid

UGT= UDP--D-Glucuronsyltransferase

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Glucuronidation of Aniline

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Glucuronidation of p-Hydroxyacetanilid

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SULFATE CONJUGATION

• Conducted by the soluble enzyme sulfotransferase• Endogenous donor molecule to conjugation is

3’-phosphoadenosine-5’-phosphosulfate (PAPS)• Conjugates are ethereal in character• Noninducible

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3’-Phosphoadenosine-5’-phosphosulfate (PAPS)

The cytosolic enzyme sulfotransferase conducts the donation of sulfate from the endogenously synthesized PAPS to various substrates to form sulfate conjugates. An example of such substrate is acetaminophen.

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SYNTHESIS OF PAPS

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Sulfate Conjugation of p-Hydroxyacetanilid

PAP: 3’-phosphoadenosine- 5’-phosphate

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AMINO ACID CONJUGATION

RCOOH + CoA-SHAcid:CoA ligase

RCO-S-CoA

RCO-S-CoA + NH2CH2COOH

RCONHCH2COOH

N-acyl transferase

ATP

Glycine

Glycine conjugate

(mitochondria)

Acyl CoA

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Salicycluric Acid is the Glycine Conjugate of Aspirin

Salicyluric acid, the glycine conjugate of salicyclic acid, is the main metabolite of aspirin. Approximately 76% of aspirin is metabolized through amino acid conjugation.

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N-ACETYLATION

• A soluble enzyme• Isoniazid is a substrate• Genetic variation occurs

– Some individuals are fast acetylators– Some individuals are slow acetylators

• Acetyl coenzyme A is the endogenous donor molecule

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Acetyl CoA

Various acetylases, for examples, choline acetylase and N-acetyl transferase, all soluble enzymes, conduct the transfer of the acetyl group of acetyl CoA to various substrates. For example, N-acetylation of isoniazid. Genetic polyporphism occurs with N-acetyltransferase.

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N-Acetyltransferase

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METHYLATION

S-Adenosylmethionine

Cytosolic enzymes such as catechol-O-methyl transferase (COMT) and phenylethanolamine-N-methyl transferase (PNMT) conducts the donation of the methyl group from the endogenously synthesized SAM to various substrates to form methylated conjugates. Norepinephrine is N-methylated by PNMT to form epinephrine. Norepinephrine, epinephrine, dopamine, and L-DOPA are O-methylated by COMT.

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Methyltransferases

• A family of soluble enzymes that conducts

– N-methylation; N-CH3

– O-methylation; O-CH3

– S-methylation; S-CH3

• S-adenosylmethionine (SAM)is the endogenous donor molecule. It is demethylated to S-adenosylhomocysteine

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N-Methyltransferases

PNMT- Phenylethanolamine-N-methyltransferase

Norepinephrine EpinephrinePNMTSAM

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O-Methylation Of Catecholamines

COMT- catechol-O-methyltransferase

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O-Methylation of Norepinephrine

COMT- catechol-O-methyltransferase

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S-Methylation of 6-Mercaptopurine

TPMT - thiopurinemethyltransferase; some individuals are deficient in this enzyme that is critically important for the metabolism of this agent

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GLUTATHIONE CONJUGATION

Glutathione

-glutamyl-cysteinyl-glycine

Active site of a GST:Nucleophile

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DRUG INTERACTION WITH GLUTATHIONE

mercapturate metabolite of drug

(S-substituted glutathione conjugate)

Glutathione-S-transferase

glutamyl transpeptidase-ץ

Cysteine-glycine conjugateCysteinyl glycinase

Cysteine conjugateN-acetylase

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MERCAPTURIC ACID FORMATION

• Conjugation of substrate to glutathione by the enzyme glutathione transferase

• Hydrolytic removal of glutamic acid by glutamyl transpeptidase

• Hydrolytic removal of glycine by cysteinyl glycinase• Acetylation of the cysteinyl substrate by

N-acetyltransferase to form the N-acetylated cysteinyl conjugate of substrate; substrate referred to as a “mercapturate”

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METABOLISM OF NAPHTHALENE BY GLUTATHIONE CONJUGATION

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TRANSULFURATION

Inactive

Mediated bymercaptopyruvate sulfurtransferase

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Q & AQ & A

Those are my thoughts.Those are my thoughts.– What are yours?What are yours?

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THANK YOU