Pharmacokinetics 2 Flashcards
Describe drug metabolism
Mainly occurs in the liver in 2 phases:
- Phase 1 metabolism
- Phase 2 metabolism
This is not always linear, not all drugs need to pass Phase 1 to be subject to Phase 2 metabolism.
Liver
Contains the highest concentration of enzymes that are capable of metabolising drugs in the body.
What does Phase 1 metabolism tend to be involved with ?
Functionalisation reactions
Introducing or revealing reactive chemical moieties / groups onto a drug compound.
Produces more reactive products.
Phase 1 metabolism
Generally oxidation, reduction or hydrolysis
- Introduce/reveal a reactive chemical group
- “Functionalisation”
Products are often more reactive
Why are reactive products produced in Phase 1 metabolism ?
These reactive products can bind on and introduce a conjugate.
This adds on large clunky groups to the chemical compound to make it more soluble in water.
If it is more soluble in water, it is more likely to be excreted out by the kidneys, eliminated by the body.
Phase 2 metabolism
Synthetic, conjugative reactions
Hydrophilic, inactive compounds generated (usually)
What are cytochrome P450 enzymes ?
Mixed function mono-oxygenases
Throughout the body, extensively in the liver.
57 human genes coding for CYP P450 enzymes.
Function of cytochrome p450 enzymes
Biosynthesis of steroids, fatty acids and bile acids.
Metabolism of endogenous and exogenous substrates.
Main function of metabolism
To make reactive metabolites that can be eliminated out from the body as easily as possible.
They need to water soluble or so bulky that the body just rejects them out in the faeces and they get eliminated.
What is involved in Phase 1 metabolism ?
The Cytochrome P450 enzymes which are found in high concentrations in the liver.
Metabolism of Paracetamol - conjugation step
Paracetamol is conjugated either with
- sulphate conjugate
- glucoronide conjugate
without the need for Phase 1 metabolism
Metabolism of paracetamol
A small amount of paracetamol undergoes metabolism by cytochrome P450 enzymes.
This produces reactive compounds which need to be detoxified.
Describe the degradation and elimination of the toxic metabolite produce from metabolism of paracetamol
2 pathways:
1:
- Normal glutathione levels
- Combination with glutathione
- Conjugation and excretion
2:
- Too much toxic metabolite
- Depleted glutathione levels
- Combination with hepatic proteins
- Toxicity + irreversible liver damage
How to solve toxicity caused by metabolism of paracetamol ?
Replenish glutathione levels
- give acetylcysteine which is the precursor to glutathione
More glutathione to detoxify the toxic metabolite.
Key examples of metabolism
Metabolism of paracetamol
Warfarin and phenobarbital
Grapefruit juice and statins
Warfarin and Phenobarbital
Phenobarbital upregulates the expression of cytochrome p450 enzymes quite substantially.
Warfarin is metabolised by Cytochrome P450s.
So if they are co-prescribed you would see a decrease in effectiveness of warfarin.
Grapefruit juice and statins
NOT to take statins with grapefruit juice.
Simvastatin metabolised by CYP3A4 in gut wall and liver.
High 1st pass metabolism - around 5% reaches circulation.
Grapefruit juice blocks CYP3A4.
So increased amount of statins reaches the bloodstream, could be toxic.
What is the function of different routes of metabolism ?
Different routes of metabolism allow for patient specific choices to be made.
e.g. genetic variability, disease state and other treatments
Vecuronium - metabolism/elimination
Liver - eliminated via urine and bile
Atacurium - metabolism/elimination
Spontaneous degradation in plasma
Mivacurium - metabolism/elimination
Plasma cholinesterase
Feature of metabolites
Metabolites can be active or toxic
Feature of metabolism - summary
Genetic variability in metabolic enzymes occurs and expression of metabolic enzymes can be induced and/or inhibited.
Competition for metabolic enzymes occurs and metabolic pathways can be saturated.
What can metabolism affect ?
Metabolism can affect the bioavailability of drugs.
