one conjugation

8/2/2019 one Conjugation

1/10

1

Drug Metabolism

Phase II Transformations

Acetyl Conjugation

Like methylation, acetylation results in a less hydrophilc metabolite (e.g.; anamine is converted into an amide).

The physiological consequence is that the it may deactivate a drug or its Phase Imetabolites (if they are active as well).

Acetylation involves two steps:

1. Cofactoracetyl-CoA activates acetyltransferase

2. acetytransferase transfers the acetyl group to the substrate.

Drug Metabolism


Acetyl Conjugation cilastin is an inhibitorof dehydropeptidase, which hydrolyzes the antibacterial

agent imipenem.

Thus, cilastin prevents metabolism of imipenem when the two agents are

coadministered.


2/10

2

Drug Metabolism


Acetyl Conjugation

Sometimes acetyl conjugation occurs to detoxify substances (e.g. anilines) that

could further produce other harmful metabolites!

Drug Metabolism


Amino Acid Conjugation

Amino acid conjugation occurs for a variety ofcarboxylic acids and the result is

the formation of an amide bond to an amino acid, usually glycine orglutamine.

The reaction is catalyzed by amino acid acyl transferase enzymes.

Glycine is the most common conjugating amino acid in mammals.


3/10


4/10


5/10

5

Drug Metabolism


Glucuronidation

There are 4 general classes of glucuronides that are produced:

O-Glucuronide

hydroxyl(alcohol, phenol)

carboxylic acid

N- Glucuronide

amine

amide

sulfonamide : R-SO2NH-R

S- Glucuronide

sulfhydryls (e.g. thiols) R-SH

C- Glucuronide

1,3-dicarbonyls

Drug MetabolismPhase II Transformations

O-Glucuronidation

Silverman, p. 331


6/10

6


N-Glucuronidation

Silverman, p. 331


S- and C-Glucuronidation

Silverman, p. 331


7/10

7


Sulfate Conjugation

Sulfate Conjugat ionis less prevalent than glucuronidation, presumably due to the

lower availability ofinorganic sulfate in mammals.

The most common substrates that undergo sulfate conjugation are phenols.


Sulfate Conjugation

There are three steps that occur with sulfate conjugation:

1. activation of inorganic sulfate by ATP

2. phosphorylation of the 3 OH to generate the sulfation cofactor.

3. conjugation with the substrate to yield the sulfate.


8/10

8


Glutathione Conjugation

Glutathione (GSH) is a tripeptide and is found in nearly all mammalian tissues.

Conjugation of this sort occurs in the cytoplasm of most cells, especially in the liver

and kidney where the GSH concentration is 5-10 mM.

Its apparent function is to scavenge potentially harmfulelectrophiliccompounds;

(either xenobiotics or their metabolites).

This chemical basis for its function its reactive nucleophilic thiol group.

Drug Metabolism



The conjugation is mediated by the enzyme glutathione transferase (GST)

although with more reactive electrophiles the conjugation may occur

nonenzymatically.

Glutathione conjugation differs from the previous Phase II reactions since

electrophiles (rather than nucleophiles) are subject to conjugation.

Glutathione can to conjugate to many types of electrophilic species

Well examine these two types:

alkyl halide equivalents/epoxides (SN2 reactions!)

activated aryl halides (SNArreactions!)


9/10

9

Drug Metabolism



SN2-type reactions:

Drug Metabolism



SNAr-type reactions: general mechanism

SNAr-type reactions: metabolism of azathiprine:


10/10

10

Drug Metabolism



Once formed, GSH conjugates are rarely excreted directly but more often undergo acouple more steps of metabolism to be excreted as N-acetylcysteine conjugates.

This pathway is considered by some to be Phase III metabolism.

one conjugation

Documents