Variable Drug Metabolism Flashcards
How do drug-drug interactions cause variations in drug metabolism?
2 drugs competing for the same enzyme
Systemic exposure to 1 or both is altered
How do drug-diet interactions cause variations in drug metabolism?
Active compounds of certain foods can be P450 substrates
- grapefruit juice and CYP3A4
How does genetic variation in gene encoding cause variations in drug metabolism?
Genetic variation can render an enzyme useless / cause a loss in function to the enzyme
What other factors affect drug metabolism?
Underlying disease and environment / lifestyle - smoking, alcohol
What is enzyme induction?
Where the enzymatic activity is increase by inducing increased hepatic protein expression - in liver
What is auto induction?
Where a drug induces expression of CYP isoforms which is responsible for its own metabolism
Give an example of auto induction.
Rifampicin - anti-tuberculosis drug - induces CYP3A4 hepatic expression and is also the substrate for CYP3A4
What’s the problem with drug-drug interactions?
Exposure of the drug is increased, above therapeutic window and put patient at risk of toxicity / adverse drug response
Give an example of drug-drug interactions. What’s the risk?
6-mercaptopurine and allopurinol
Allopurinol inhibits xanthine oxidase
Results in bone marrow toxicity - can become fatal as 6-mercaptopurine clearance is blocked
Give an example of drug-diet interactions
Grapefruit juice - CYP3A4 inhibitor
Inhibits simvastatin clearance and hence becomes toxic
What percentage of drugs does CYP2D6 metabolise in some way?
> 55% of all drugs
Give an example of genetic variation
Ultra-rapid , extensive , intermediate and poor metaboliser
Affects the rate of metabolism of drugs - inherited from parents - by CYP2D6
How is codeine metabolised?
Metabolised to morphine - 100x more potent analgesic
Dealkylatyed via CYP2D6 - oxidised in presence of NADPH
What is irintecan? How is it metabolised?
Colorectal cancer drug - pro drug metabolised to SN-38
Irinotecan is hydrolysed to give SN38
How is SN-38 metabolised?
Undergoes glucuronidation and is excreted in bile to form SN-38-glucuronide
What does SN-38 toxicity result in?
Severe diarrhoea and neutropenia - significant decrease of white blood cells
Give examples of toxic phase 1 metabolites
Epoxides
Hydroxylamines
Quinoneimines
Free radicals
What do toxic phase 1 metabolites result in?
Bind to tissue macromolecules
Lipid peroxidation
Oxidative stress
Causes;
Cell damage / death
Tissue necrosis
Inflammation
What’s the antidote to paracetamol overdose?
N-acetyl cysteine
Only effective up to 16hrs after initial dosing of paracetamol
What does NAPQI - paracetamol metabolite - cause?
Necrosis
Liver damage
Hepatitis
DEATH
What other pathways does paracetamol undergo to prevent NAPQI? What enzymes?
UDP-glucuronosyl transferase + UDPGA
-OH is glucuronidated which is more polar and more readily excretable
Sulphation via Sulphotransferase + PAPS
How can NAPQI be metabolised?
Via Glutathione S-transferase
It can then be excreted
What does N-acetylcysteine do?
Replenishes tripeptide needed for glutathione transferase reaction, allowing NAPQI to be metabolised and removed from the body
What is isoniazid? What’s the issue with it?
Used to treat tuberculosis
Causes hepatotoxicity in 1-2% of people
What’re slow acetylators?
Have lower expression of NAT enzymes in their liver hence have increased risk of hepatotoxicity
What’re the risks slow-acetylators face with isoniazid?
Isoniazid - also hydrolysed to hydrazine - cannot be acetylated
Hydrazine is hepatotoxic
What is clopidigrel?
Anti-platelet used to prevent heart attacks and stroke in high risk patients - thins blood
How is clopidogrel given?
Given as a pro drug and is metabolised to its active thiol metabolite
What risks surround clopidogrel?
Sub-optimal metabolism causes reduced efficacy and reduces effectiveness of the drug
What enzymes metabolise clopidogrel?
CYP2C19 enzymes oxidise twice to form active compound
Also metabolised by hydrolysis by carboxylesterases to inactive form
How much of clopidogrel is metabolised to form active/inactive form?
15% ACTIVE FORM
85% INACTIVE FORM
What happens when CYP2C19 is inhibited in some way?
Clopidogrel then follows hydrolysis by carboxylesterases to form inactive compound only
Hence no response
What % of the population cannot oxidise clopidogrel effectively?
3-4% means they cannot metabolise clopidogrel to its active form - to stop a heart attack/stroke
