Drug Metabolism Chapter No 5

 Metabolism means Catabolism (breaking down of substances)

Anabolism (building up or synthesis of substances)

But when we speak about drug metabolism, it is only 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


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 to make them more active ,less active and finally inactive and to leave the body.

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

Pathways of drug metabolism Phase I reactions:

Hydroxylation oxidation Reduction Hydrolysis

Phase II reactions: glucuronidiation

Sulfation Acetylation Methylation
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PHASE I AND PHASE II REACTIONS IN DRUG METABOLOISN

PHASE I REACTIONS
Convert the parent drug to a more polar (watersoluble) and/ or more reactive product by unmasking or inserting a polar group such as -OH, -SH, -NH2

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

Both types of reaction convert relatively lipid-soluble original drug molecules into more watersoluble metabolites that are more easily excreted

PHASE I REACTIONS Aromatic Hydroxylation

To

answer this question we need to examine the structure of diazepam . It is extremely important to remember that chemical structure is intimately linked to reactivity.

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O R C

H C H R' R

O C

H C OH R'

CH3 N

O Hydroxylation

CH3 N

O OH N-Demethylation Cl

H N

O OH N

Cl

N Ph Diazepam (Sustained anxiolytic action)

Cl

N Ph Temazepam (Short duration)

Ph Oxazepam (short duration)

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

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S-Oxidation (Drugs containing)

O R1 S R2 R1 S R2 Sulfoxide

O R1 S R2 O Sulfone

S R1 C R2 R1

O C R2

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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 of C=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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Reduction of Nitro & Azo Compounds

H R C H Nitro N

O R O

H C H Nitroso N O R

H C H N

H R OH

H C H 1 amine N

H H

Hydroxylamine

R1

R2

R1

H N

H N

R2

R1

NH2

H2N

R2

Azo

Hydrazo

Two 1 amines

NH

NH2 + N N2

Azido

Amine

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P450 and its Function in Drug Metabolism

The cytochrome P450 is a large and diverse group of enzymes 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 oxygen atom is reduced to

O N

H N O N

CYP450
O H OH O

N O

H
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R1 CYP450

R1 Spontaneous

R1

O OH R1 Epoxide hydrolase Aromatase OH OH R1 Glutathione

OH

R1

OH OH

S Glutathione R1 Macromolecule
OH

Macromolecule

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Oxidation involving C-O System (O-Dealkylation)

OH O H3C H 3C O CH2 N N NH2

us eo tan on Sp

O H 3C H3C O

CH3 N N NH2 NH2 H 3C H 3C O

CY P4 50

NH2

OH N N NH2 NH2

Trimethoprim O-Dealkylation

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Oxidative Dehalogenation

H R C Cl Cl

CYP450 R

OH C Cl Cl

O Spontaneous O R C R C +H2O Cl OH + + H Cl H Cl

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 aniline NO2 NH2 Chloral hydrate trichloroethanol

Hydrolysis:
Ester-C-O and amides-C-N Acetylcholine choline +acetate(ester) Procainamide (lidocaine) (amide)
OH O O H3C O OH OH O OH

+
H3C O

Aspirin

Salicylic Acid

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H2N H N O CH3 N CH3

Slow Hydrolysis

Procainamide
H2N H2N O O CH3 OH

CH3

Rapid Hydrolysis

Procaine
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Metabolic Oxidation of Alkene

O Epoxide hydrolase OHOH

Alkene

Epoxide

trans dihydrodiol derivative

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Oxidation by soluble enzyme in cytosol or mitochondria of cells e.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 Drug

Metabolism)

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-drug
Chloral 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 to form 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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Phase II Conjugation Reaction 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

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Age: In elderly metabolism is reduced because liver mass , and

liver blood flow are decreased

Pregnancy: Hepatic metabolism is increased

Disease: Acute inflammatory disease of liver (viral ,alcoholic)

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

Food: some specific dietary factors induce drug metabolizing

Factors affecting drug metabolism

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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

Hydrolytic Reactions Esters and amides Epoxides and arene oxides by epoxide hydrase 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-oxide formation, N-hydroxylation) C-O (O-dealkylation) C-S (S-dealkylation, S-oxidation, desulfuration)

Phase II Conjugation

Phase I Functionalization

Drug Metabolism
Glucuronic acid conjugation Sulfate Conjugation Glutathion or mercapturic acid Acetylation Methylation

Oxidation of alcohols and aldehydes Miscellaneous Reduction Aldehydes and ketones Nitro and azo Miscellaneous