Tutorial 3 - Drug Metabolism Flashcards
Fill in the blanks:
The major site of metabolism of foreign chemicals/xenobiotics in man is the …
Cytochrome P450 enzymes from a central part of the drug metabolising system and are found in the… . Its principal role is in …. of chemicals and hence requires … and the coenzyme… .
Phase 1 metabolism typically involves … or … reactions. Give two examples; … & …
Phase 2 metabolism typically involves … reactions which … the polarity of drugs which facilitates excretion. Give two examples; … & …
Glutathione is a tripeptide consisting of … which is most abundant in the … and reacts with … chemical intermediates.
The major site of metabolism of foreign chemicals/xenobiotics in man is the liver.
Cytochrome P450 enzymes from a central part of the drug metabolising system and are found in the mitochondria . Its principal role is in oxidation of chemicals and hence requires O2 and the coenzyme NADPH .
Phase 1 metabolism typically involves oxidation or reduction reactions. Give two examples; hydroxylation & ester hydrolysis
Phase 2 metabolism typically involves conjugation reactions which increase the polarity of drugs which facilitates excretion. Give two examples; amino acid conjugation & suphate conjugation.
Glutathione is a tripeptide consisting of glycine, cysteine and glutamine which is most abundant in the liver and reacts with electrophilic chemical intermediates.
Where is paracetomol metabolised?
It is largely metabolised in the liver which results in excretion of paracetamol as non-toxic metabolites.
What type of drug is paracetomol?
A widely used analgesic and anti-pyretic drug (reduces fever)
How is paracetomol typically administered?
It is taken orally, absorbed and distributed throughout the body enabling pain and fever relief.
What organ can be damaged by taking an overdose of paracetomol?
It can cause liver damage after over-dosage.
NAPQI (product of paracetomol phase I metabolism) reacts with proteins in the liver and therefore can cause damage
What enzymes mediate Phase I metabolism of paracetomol?
Phase 1 metabolism of paracetamol is mediated by CYP450s
What is formed after Phase I metabolism of paracetomol?
10% of dose
- Reactive intermediate, NAPQI.
- See picture attached
20-40% of dose
- Sulphates
60-80% of dose
- Glucuronides
NAPQI is electrophilic and will be furthered metabolised and detoxified by a phase 2 reaction. Discuss this reaction.
NAPQI is electrophilic
- detoxified in glutathione conjugation
- prevents NAPQI from binding
Based on the metabolic products of paracetamol stated above, suggest what could be used to salvage the toxicity in a case of acute poisoning and explain your mechanistic reasoning.
Oral/I.V. N-acetylcysteine
OR
Oral methionine/S-adenosyl-methionine
- trying to get patient to synthesis their own glutathione
- relieves saturation of sulphation pathway
A radioactive-labelled paracetamol mass balance study is conducted to study the distribution and metabolism of paracetamol in the rat. Which of the metabolites you have discussed above would you expect to predominantly find in the;
- bile
- urine
- serum
Bile
- Glucuronides
- Glutathione
Urine
- Sulphates
- Glucuronides
Serum
- Parent
The plasma half-life of paracetamol in patients with liver damage due to overdosage is over twice that in normal human subjects after a therapeutic dose. Interpret this information given what you know about the metabolism of paracetamol.
The major route of metabolism for the reactive intermediate, NAPQI, is glutathione conjugation followed by transformation to a mercapturate will deplete glutathione levels.
This results in increased covalent binding of NAPQI to proteins/nucleic acids causing liver damage and/or the NAPQI can be reduced back to paracetomol, thus increasing the half-life.
All of the above result in a higher plasma level of unmetabolised paracetomol, and hence longer half-life.
Acetanilide is a pro-drug of paracetamol. Acetanilide causes methemoglobinemia and as a result was removed from the market and replaced with paracetamol. Explain the term pro-drug and show what reaction is involved in the transformation of acetanilide to paracetamol.
A pro-drug is a biologically inactive compound which can be metabolized in the body to produce a drug.
