Acetaminophen

metabolism
Ahmad Izzuddin Mohd Rosli

ACETAMINOPHEN
METABOLISM
Paracetamol is primarily metabolized in the
liver
We
look
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

will
into

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

(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

NAP
QI

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

NAP
QI

Hepatic necrosis

NAPQI

Abundance of
toxic NAPQI
cause

Renal failure
But it
can be
revers
ed
using

 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