Introduction of Drug Metabolism Flashcards
What does ADME stand for?
Absorption
Distribution
Metabolism
Excretion
Stages of drug metabolism
Stage 1 (modification) e.g. oxidation - Hydrophobic drug Stage 2 (Conjugation) e.g. methylation - Make drug hydrophillic Stage 3 (Excretion) e.g. Efflux from the cell
What is polymorphism?
Genetic changes
What are xenobiotics?
substances which are found in the body which are not naturally produced in the body
How is drug metabolism regulated?
By nuclear receptor which live in the cytoplasm of the cell
What is functionalisation?
When by phase I reaction, the functional group is exposed (e.g. -OH) so it can undergo conjugation
What happens during phase II drug metabolism?
Detoxification of drug
Gives rise to water soluble and easy to excrete products
Name an anti-epileptic drug
Phenytoin
Explain the functionalisation of phenytoin
Phenytoin (highly lipophillic) -CYP-> 4-hydroxy-phenytoin (slightly soluble in water) -UGT + UDP-GA-> 4-hydroxy-phenytoin-glucuronide (very soluble in water)
What is the most common form of phase I drug metabolism
oxidation by Cytochrome p450
Describe flavin-containing monooygenase (FMO)
A type of oxidation enzyme
Membrane bound flavin mononucleotide/ flavin adenine nucleotide containing protein
High concentrations in the liver
Subcellular location: smooth endoplasmic reticulum
Cofactors - NADPH and molecular oxygen (O2)
What is FMO3?
A gene which provides instructures to make FMO
Disease related to polymorphism in FMO3
Fish odour syndrome
- secrete lots of TMA in urine, sweat, breath
- severe psychological consequences
Describe cytochrome p450
Terminal oxidase in an electron transfer system of the endoplasmic reticulum
Functions of cytochrome p450
- steroid biosynthesis
- bile acid biosynthesis
- xenobiotic metabolism
- fatty acid metabolism
What allows the removal of an electron from NADPH?
p450 OxidoReductase (POR)
POR effects
steroid synthesis in adrenal glands and gonads Cholesterol synthesis Metabolism in the liver of: - steroids - drugs - other xenobiotics
What is the main type of p450 nomenculture?
CYP2
Type of anti-histamine drug
Terfenadine
Type of antidepressant
Amitriptyline
Describe sulphotransferases
Phase 2 metabolism Conjugating moiety: sulphate Location: high concentrations in the liver and intestine and also found in platelets Subcellular location: cytosol Cofactors: PAPS
Describe N-acetyl transferases
Phase 2 metabolism
Conjugating moiety: acetyl group
Cofactors: acetyl CoA
Mainly in the liver and in the gut and lung
Describe UDP-glucuronyltransferases (UGT)
Conjugating moiety: glucuronic acid
Membrane bound protein
High concentrations in the liver, some in the gut and other tissues
Subcellular location: smooth endoplasmic reticulum
Cofactors: UDP-GA
Why are glucuronide good in drug metabolism?
They are readily excreted
What does the use of cytochrome p450 do to the drug?
Make electrophiles
What does glutathione do to the electrophiles?
Make less toxic conjugates
What catalysts the glutathione reaction?
Glutathione S-transferases (GST)
What happens to the less toxic conjugates?
Excreted in urine or bile
Metabolised further in the mercapturic acid pathway
Where are glutathione transferase found?
Cytoplasm Mitochondria Endoplasmic retriculum Nucleus In all tissues and eukaryotes
Effects of oltipraz
Inhibit phase 1 p450 enzymes and induces phase 2 enzymes
Effects of polymorphisms in drug metabolism
Mutations in genes for drug metabolising enzymes - leading to increased or decreased enzyme activity
Describe a common food-drug interaction
Bananas and ACE inhibitors
- ACE inhibitors increase potassium in your body
- too much potassium can cause irregular heartbeat Andy heart palpitations
Give the stages of drug development
1) target identification
2) target assay construction and screening
3) target validation
4) phase 1 safety
5) phase 2 efficacy safety
6) phase 3 efficacy safety
7) FDA review and approval
How long does drug devlopment take
12-15 years
Common effect of chemotherapy
Induces p450
