Acetaminophen metabolism

Ahmad Izzuddin Mohd Rosli

ACETAMINOPHEN METABOLISM
Paracetamol is primarily metabolized in the liver
We will look
into this!

For a drug to be eliminated from the body, it is important for the

drug to be sufficiently hydrophilic. Drug will be more soluble in
water so it is easier to get eliminated from the body.

To do so, there are 2 phases of drug

metabolism reactions
We
will
look
into
this!

adding or unmasking
a hydroxyl group

adding a large polar

group

PHASE 2: CONJUGATION

5%

A. MAJOR PATHWAY

uridine diphosphoglucuronosyl
transferase

Cause conjugation of
glucuronide group on the
acetaminophen

Glucuronide conjugate
(NON TOXIC)

eliminated directly
via urine

90%
Enter our
body
converted to

Cause conjugation of
sulphate group on the
acetaminophen

Sulphate conjugate

ELIMINATION

Conjugation result in increase hydrophilicity.

Drug more soluble in water and easily eliminated out of
the body.

(NON TOXIC)

PHASE 2: CONJUGATION (MINOR PATHWAY)

excessive amount of acetaminophen in the liver can saturate the
sulphation and glucuronidation pathways so the acetaminophen is
processed through another pathway, the cytochrome P-450 system

5%
enter CYP450
system

Cyp450-isozymes responsible for

biotransformation of many drugs via
oxidation

At therapeutic doses, NAPQI will undergo this

pathway, the normal pathway

THERAPEUTIC DOSES: NORMAL PATHWAY

NAPQI will be inactivated through
conjugation of glutathione

At toxic doses, NAPQI will

undergo this pathway

AT TOXIC DOSES
NAPQI production increase!

NAPQI
NAPQI

NA
PQI

NAPQI production exceed the amount of glutathione produced

Glutathione is not enough to inactivate the NAPQI

NAPQI

Exceed
**********************************

inactivate

GLUTATHIONE

 NAPQI production increase and cause

depletion of hepatic glutathione
Glutathione being used up because
rate glutathione utilised > rate
glutathione formed

exceed
NAPQI
inactivate

GLUTATHIONE

AT TOXIC DOSES
Reactive quinone in NAPQI structure highly
succeptible to thiol nucleophilic attack from the
liver protein
glutathione depletion
cause the reaction to
move to this pathway

NA
PQI

Hepatic necrosis

NAPQI

Abundance of toxic
NAPQI cause

Renal failure

Hepatic necrosis. toxic injury to the liver with sudden and precipitous onset,
marked elevations in serum aminotransferase levels, and early signs of hepatic (or
other organ) dysfunction

or failure despite minimal or no jaundice

-livertox.nih.gov/Phenotypes_ahn.html

Renal failure. kidneys fail to adequately filter waste products from the blood.

N-acetyl cysteine - used to counteract acetaminophen and carbon monoxide

poisoning

adduct is a complex that forms when a chemical binds to a biological molecule,

such as DNA or protein.

Thank you