Drug Metabolism OK

7/30/2019 Drug Metabolism OK

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Drug MetabolismChapter No 5


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Metabolism means Catabolism (breaking

down of substances)

Anabolism (building up or synthesis of

substances)

But when we speak about drug metabolism, it isonly catabolism

That is drug metabolism is the break down of drug

molecules

So what is building the drug molecules? We use

the word synthesis, then

Drugs are synthesized in laboratory and thus is not

an endogenous event


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Drug metabolism (biotransformation)It is the type of chemical reactions which

leads to modification of drugs

Drugs are converted from one form to an other tomake them more active ,less active and finallyinactive and to leave the body.

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How Do Drugs Work?

Drugs are distributed throughout the body by the blood

and other fluids of distribution. Once they arrive at the

proper site of action, they act by binding to receptors,

usually located on the outer membrane of cells, or on

enzymes located within the cell.

Usually results in loss of pharmacological activity

Sometimes may be equally or more active than parent


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Phase I reactions:Hydroxylation

oxidation

Reduction

Hydrolysis

Phase II reactions: glucuronidiationSulfation

Acetylation

Methylation

Pathways of drug

metabolism


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PHASE I AND PHASE II REACTIONS

IN DRUG METABOLOISN


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Convert the parent drug to a more polar (water-

soluble) and/ or more reactive product by

unmasking or inserting a polar group such as-OH, -SH, -NH2

PHASE I REACTIONS


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PHASE II REACTIONS

increase water solubility by conjugation of the

drug molecule with a polar moiety such as

glucuronate, sulfate, acete, glutathione and

methyl groups


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Both types of reaction convert

relatively lipid-soluble original

drug molecules into more water-

soluble metabolites that are

more easily excreted


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Aromatic Hydroxylation

To answer this question we need to examine the

structure ofdiazepam .

It is extremely important to remember that chemical

structure is intimately linked to reactivity.

PHASE I REACTIONS


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N

N

O

Ph

Cl

CH3

N

N

O

Ph

Cl

CH3

OH

N

HN

O

Ph

Cl

Diazepam(Sustained anxiolytic action)

Hydroxylation

Temazepam(Short duration)

Oxazepam(short duration)

N-Demethylation OH

The metabolite may exhibit either a different potency orduration of action or both to the original drug.

R C C R'

O H

H

R C C R'

O H

OH


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R1 C R2

S

R1 C R2

O

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R1 S R2 R1 S R2

O

R1 S R2

O

O

Sulfoxide Sulfone

S-Oxidation (Drugs containing)


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Reductive Reactions

Reductive Reactions

Bio reduction of C=O (aldehyde and keton) generates alcohol

(aldehyde 1o alcohol; ketone 2o alcohol)

Nitro and azo reductions lead to amino derivatives

Reductive cleavage of disulfide (-S-S-) linkages and reduction ofC=C are minor pathways in drug metabolism

Reductive dehalogenation is a minor reaction primarily differ from

oxidative dehalogenation is that the adjacent carbon does not

have to have a replaceable hydrogen and generally removes one

halogen from a group.

(Then All products converted into glucuronidated, carboxylic acid

etc become water soluble compounds)


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R C N

H

H

R C N

H

H

H

H

H

OH

R C N

H

H

R C N

H

H

O

O

1 amineHydroxylamineNitrosoNitro

O

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N N R2R1 R1 NH2 H2N R2+

Azo Two 1 amines

HNR1

Hydrazo

HN R2

N NR

Azido

NH2R

Amine

NH + N N

N2

Reduction of Nitro & Azo Compounds


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The cytochrome P450 is a large and diverse group ofenzymes that catalyze the oxidation of organic substances

The most common reaction catalyzed by cytochromes P450 is

a monooxygenase reaction, e.g., insertion of one atom of

oxygen into an organic substrate (RH) while the other oxygenatom is reduced to

P450 and its Function in Drug Metabolism

N

N

H

H

O

O

O

N

N

H

H

O

O

OOH

CYP450


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R1 R1

OH

R1

O

R1

OH

OH

R1

SGlutathione

R1

Macromolecule

Spontaneous

Epoxide hydrolase

Glutathione

Macromolecule

R1

OH

OH

Aromatase

CYP450

OH

OH


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O

O

O

NH2

NH2

N

N

CH3

H3C

H3C

O

O

O

NH2

NH2

N

N

CH2

H3C

H3C

OH

O

O

NH2

NH2

N

NH3C

H3C

OH

Sponta

neousCY

P450

Oxidation involving C-O System (O-Dealkylation)

Trimethoprim O-Dealkylation


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R C

H

Cl

Cl

R C

OH

Cl

Cl

R C

O

Cl

R C

O

OH+

H Cl

+H2O

CYP450

H Cl

+

Spontaneous

Oxidative Dehalogenation

Make the drug more polar more water soluble. (oxidation,reduction, hydrolysis)

Oxidation reaction:introduces functional group (OH,NH2,SH)


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Reduction Reactions:

nitrobenzene anilineNO2 NH2

Chloral hydrate trichloroethanol

Hydrolysis:

Ester-C-O and amides-C-NAcetylcholine choline +acetate(ester)Procainamide (lidocaine) (amide)

H3C O

O

O

OH

H3C OOH

O

OH

OH

+

Aspirin Salicylic Acid


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CH3

CH3N

H2N

O

O

CH3

CH3N

H2N

O

H

N

Procainamide

Procaine

H2N

O

OH

Slow Hydrolysis

Rapid Hydrolysis


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Metabolic Oxidation of Alkene

EpoxideAlkene trans dihydrodiol derivative

Epoxide hydrolaseOOHOH


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Oxidation by soluble enzyme in cytosol or mitochondria

of cellse.g

1. dehydrogenases and oxidases

Ethanol acetaldehyde acetic acid.

Methanol formaldehyde formic acid

CH3CH2OH CH3CHOCH3COOH

2. monoamide oxidase(noradrenaline)

3. Hypoxanthine xanthine uric acid

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Characteristics of Phase I Products(Result of DrugMetabolism)

1. Inactivation (abolish the activity)Oxidation of Phenobarbital and alcohol

Hydrolysis of acetylcholine

2. Conversion of active drug to another active one.Diazepam oxydiazepam

Codeine , heroin Morphine

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3. Conversion of drug to toxic metabolites:Paracetamol acetaminopen (hepatic toxicity)

Halothane metabolite hepatotoxicity

4. Activation of pro-drugChloral hydrate trichloroethanol

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Phase-II Metabolism

It involves union of the drug with one of several

polar(water soluble ) endogenous molecules that

are product of intermediatory metabolism toform water soluble conjugate which is readily

eliminated by the kidney or if the molecular

weight is more than 300 in the bile

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Subsequent reaction in which a covalent linkage

is formed between a functional group on the

parent compound or Phase I metabolite and an

endogenous substrate such as glucuronic acid,

sulfate, acetate, or an amino acid

Highly polar rapidly excreted in urine and feces

Usually inactive - notable exception is morphine

6-glucuronide

Phase II Conjugation Reaction


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Factors affecting drug metabolism

Age: In elderly metabolism is reduced because liver mass , andliver blood flow are decreased

Pregnancy: Hepatic metabolism is increased

Disease: Acute inflammatory disease of liver (viral ,alcoholic) Food: some specific dietary factors induce drug metabolizing

enzymes

e.g. alcohol, charcoal grilled beef, cabbage.

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Pregnancy: Hepatic metabolism is increased

This leads to increased clearance of drugs such as phenytoin

and theophylline

Disease: Acute inflammatory disease of liver (viral ,alcoholic)and cirrhosis affect function of hepatocytes and blood flow

through the liver, this results in increased systemic availability

of drugs .

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SUMMARY OF DRUG METABOLISM


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General Metabolic Pathways

Glucuronic acid conjugation

Sulfate Conjugation

Glutathion or mercapturic acid

Acetylation

Methylation

Reduction

Aldehydes and ketones

Nitro and azo

Miscellaneous

Oxidation

Aromatic moieties Olefins

Benzylic & allylic C atoms

and a-C of C=O and C=N

At aliphatic and alicyclic C

C-Heteroatom system

C-N (N-dealkylation, N-oxideformation, N-hydroxylation)

C-O (O-dealkylation)

C-S (S-dealkylation, S-oxidation,

desulfuration)

Oxidation of alcohols and

aldehydes

Miscellaneous

Phase II -Conjugation

Phase I -Functionalization

Drug

Metabolism

Hydrolytic Reactions

Esters and amides

Epoxides and arene oxides

by epoxide hydrase

Drug Metabolism OK

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