Toxic metabolites

1. Muhammad Arslan Tahir (605)
Muhammad Shan (621)

2. Toxicology:
The branch of science concerned with
the nature, effects, and detection of
poisons.
Toxicology, the study of toxicity, is situated
at the border of chemistry, biology, and in
some cases.

3. Metabolic conversions of drugs required for therapeutic
effect, whether biotransformation lead to the formation of
toxic metabolites or to variations in therapeutic effects.
It depends on
intrinsic: (such as the genetic polymorphism of some
metabolism pathways)
extrinsic: (such as the dose, the route or the duration)
factors.

4. Biotransformation begins with the transient formation of a
reactive intermediate, whose lifetime is long enough to
allow an attack on cellular components. This occurs when
a reactive intermediate (generally radicals or electrophiles
such as a carbonium ion) is formed and reacts rapidly with
cellular macromolecules (such as unsaturated lipids,
proteins, nucleic acids…), thus leading to their
degradation and finally to cellular necrosis.

5. Examples of drugs that produce toxic metabolites:
1) Isoniazid
2) Chloramphenicol
3) Acetaminophen
4) Chloroform
5) Sulphathiazole

6. Isoniazid (INH) is highly effective for the management of
tuberculosis.
However, it can cause liver injury and even liver failure.
INH metabolism has been thought to be associated with
INH-induced liver injury.

7. Mechanism of toxicity:
• Isoniazid undergoes acetylation to form acetylisoniazid
• Acetylisoniazid undergoes hydrolysis and breaks down into
isonicotinic acid and acetylhydrazine
• Acetylhydrazine is an acetylating agent that causes hepatotoxicity.

9. Chloramphenicol is an antibiotic.
Mechanism of toxicity:
• Chloramphenicol is oxidized by CYP monooxygenase to
chloramphenicol oxamyl chloride formed by the oxidation of the
dichloromethyl moiety of chloramphenicol followed by elimination of
hydrochloric acid .
• The reactive metabolite reacts with the -amino group of a lysine
residue in CYP 15.

10. • Inhibits the enzymatic reaction progressively with time.
• This type of inhibition is a time-dependent inhibition or a mechanism
base inhibition or inactivation, and the substrate involved historically
has been called a suicide substrate because the enzymatic reaction
yields a reactive metabolite, which destroys the enzyme.

12. Belongs to the class ‘NSAIDs’
Widely used for analgesic and antipyretic activity
Hepatotoxicity due to formation of highly active metabolite
NAPQI (N-acetyl-p-benzoquinone imine)

13. Metabolism
After therapeutic doses:
• Glucuronide conjugates (52-57%)  kidney + liver
• Sulfate conjugates (30-44%)  kidney
• NAPQI (5-10%)
• Excreted unchanged (<5%)

14. NAPQI
Mostly formed in the liver, a little in kidney
Highly reactive
Primarily responsible for hepatotoxicity
Detoxification:
• Binding to sulfhydral group of glutathione (GSH)
• Excretion through urine as cysteine and mercapturic acid conjugates

15. After supratherapeutic doses:
• Sulfation pathway becomes saturated
• Glucuronidation and oxidation increases
• Excretion as unchanged also increases
After highly toxic doses:
• Glucuronidation also gets saturated
• Elimination as unchanged increases (~10%)
• Oxidation to NAPQI (>15%)

16. Excess NAPQI:
• Depletes GSH Stores
• Starts to form protein adducts through binding to cysteine groups on
cellular proteins
NAPQI primarily targets mitochondrial proteins and ion
channels leading to
• the loss of energy production
• ion misbalance
• cell death

18. Belongs to the class of ‘General Anaesthetics’
Chemically ‘trichloromethane’ (an alkyl halide)
Once widely used as inhalation anaesthetic
Not used nowadays due to toxic effects on heart and liver

19. Mechanism of toxicity:
• Chloroform undergoes CYP-mediated oxidation to trichloromethanol
• The unstable trichloromethanol loses HCl and form phosgene gas
(COCl2) which is highly reactive
• Phosgene causes oxidative stress, cell damage/death.

21. Synthetic antibacterial agent
Belongs to the class of ‘Sulphonamides’
Perform its action by dihydropteroate synthetase inhibition
Rarely prescribed nowadays due to higher incidence of
associated adverse drug reaction and toxicity

22. Mechanism of toxicity:
• Sulphathiazole is metabolized by N-acetylation
• N-acetylation increases hydrophobic character
• Reduces solubility
• Resultant metabolite can prove fatal if blocks kidney tubules
May cause:
• Crystalluria
• Kidney failure