DRUG METABOLITE-REACTION AND CONJUGATION

7/27/2019 DRUG METABOLITE-REACTION AND CONJUGATION

1/51

Drug metabolism

Metabolic processes, in general, have the

overall effect of converting drug molecules

into more polar compounds.

The effect of this have been divided into two

major categories:


2/51

Phase 1 Reaction

Human Hepatic Cytochrome Enzyme System CYP

450 s:

Oxidation is probably the most common reaction in

drug metabolism.

This reaction catalyzed by a group of membrane-

bound monooxygenase found in the smooth

endoplasmic reticulum of the liver and other extra

hepatic tissues, called the cytochrome P 450

monooxygenase enzyme system.


3/51

Phase 1 Reaction

Reactions involved in Phase 1:

A) Oxidative reactions

B) Reductive reactions C) Hydrolytic reactions.


4/51


1. Methyl substituents on the carbon skeleton of

a drug are often oxidized to form alcohols,

which may be oxidized further to carboxylic

acid.


5/51


6/51


7/51


8/51

A) Oxidative reactions:

2. The oxidation of Alkenes yield primarily

epoxide, and aromatic ring may also.


9/51


10/51


11/51

A) Oxidative reactions:

3.Aromatic hydroxylation:

For monosubstituented benzene compounds,

para hydroxylation usually predominates.

(Phenytoin)

(Acetanilide metabolite to Paracetamol)


12/51


13/51


14/51


4. Oxidation of alcohols and aldehydes:

Alcohol oxidized to aldehyde if primary, or

ketone if secondary.

Aldehyde metabolites often undergo oxidation

to generate carboxylic acid derivatives.

(Medazepam to 2-hydroxymedazepam toDiazepam)


15/51


16/51


5. O- and S-Dealkylation:

O-Dealkylation (Codeine to Morphine).

S-Dealkylation (6-Methylmercaptopurine to 6-Mercaptopurine).


17/51

O-Dealkylation:

O-Dealkylation (Codeine to Morphine)


18/51

S-Dealkylation (6-Methylmercaptopurine to 6-

Mercaptopurine).


19/51


6. N-Dealkylation:

The dealkylation of secondary and tertiary

amines to yield primary and secondary amine.


20/51

N-Dealkylation:


21/51

N-Dealkylation:


22/51


7.Oxidative Deamination :

Oxidative deamination can occur with alpha

substituted amine, by Amphetamine.


23/51

Oxidative Deamination :


24/51


8.Dehalogenation: (Halothane)

An excellent example of oxidative dehalogenation

leading to significant hepatotoxicity and

nephrotoxicity is seen with the fluorinated

inhahation anesthetics.


25/51


26/51

B) Reductive reactions

1. Carbonyl reduction: Ketones often lead to the

creation an alcohol.

(Reduction of Acetophenone)


27/51

B) Reductive reactions

2. Nitro reduction:

Aromatic nitro drugs undergo enzymatic

reduction to the amines.


28/51


29/51

3. Azo reduction:

A number of azo compounds, such as prontosil

are converted to primary amines.


30/51


31/51

C) Hydrolytic reactions

1. Hydrolysis of ester and amide:

in many drugs catalyzed by hydrolytic

enzymes.

The metabolic products formed, carboxylic

acid, alcohol, and carboxylic acid, amine.


32/51


33/51


34/51

Phase 11 Reactions (Conjugation)

1. Glucuronic Acid Conjugation:

Glucuronide formation is probably the major

and most common route for drug phase 2

metabolism to water-soluble metabolites.

Account for the major share of the conjugated

metabolites found in the urine and bile.


35/51


The formation of glucuronides involves two

steps:

1. The synthesis of an activated coenzyme

uridine-5-diphospho-D-glucuronic acid

(UDPGA).

2. The transfer of the glucuronyl moiety to the

substrate catalyzed by glucuronyltransferases

with inversion of configuration at C-1.


36/51


2. Sulfate Conjugation:

It is an important reaction in the

biotransformation of steroid hormones,

catecholamine neurotransmitters, thyroxine,

bile acid, phenolic drugs and others.

Inorganic sulfate is first converted to a high-

energy nucleotide, 3-phosphoadenosine-5-

phosphosulfate.


37/51


The sulfate group is then transferred to a

variety of aromatic and aliphatic OH, or NH2 ,

the reaction is mediated by sulfontrasferases

present in the liver and other tissues.


38/51


3. Amino acid Conjugation:

Drugs bearing a carboxylic acid group can

become conjugated to amino acids by the

formation of a peptide link.

The carboxylic acid present in the drug is first

activated by formation of a coenzyme A

thioester which is then linked to the amino

acid.


39/51


4. Glutathione conjugation:

Epoxides, alkyl halides and sulfonate can react

with the thiol group of the glutathione to give

glutathione conjugates which can be

subsequently transformed to mercapturic acid.


40/51


5. Acetylation Conjugation:

It is principally a reaction of amino groups

involving the transfer of acetyl-CoA to

primary aliphatic and aromatic amines, amino

acid , hydrazine, or sulfonamide groups.

The liver is the primary site of acetylation.

Secondary amines are not acetylated.


41/51


6. Methylation:

Methylation differs from other conjugation

processes in that the O-methyl metabolites

formed may in some cases have as great or

greater pharmacologic activity and

lipophilicity than the parent molecule e.g. the

conversion of norepinephrine to epinephrine.


42/51

The functional groups that are susceptible

to methylation are phenols, amines, and

thiols

Methylation results principally in the

formation of O-methylated, N-methylated

and S-methylated products.


43/51

The most important enzyme for

O-methylations is catechol O-methyltransferase,

which preferentially methylates the meta

position of catechols.


44/51


45/51

Problem 1:

You are hired as a consultant to a pharmaceutical companyinterested in developing a new 5-HT selective serotonin-reuptake inhibitor (SSRI), as a new family of antidepressant

drugs. Noting that fluoxetine (Prozac) is in current use, as aSSRI, how you may alter the structure of fluoxetine to prolongits half-life. You could, for example, suggest a very minorchange in the structure of fluoxetine that would retard itsmetabolism, whether by Phase I or Phase II reactions. Please

draw structures and explain your answers.


46/51


47/51


48/51


49/51


50/51


51/51

DRUG METABOLITE-REACTION AND CONJUGATION

Documents

Transcript of DRUG METABOLITE-REACTION AND CONJUGATION