Phase 2 Metabolism Flashcards
How are conjugated polar molecules eliminated from the body?
Urine
Bile
Give some examples of conjugation reactions that take place during phase II metabolism
Glucuronidation Sulphation Amino acids - glutathione - glycine - glutamine Acetylation Methylation
Which groups are commonly conjugated by glucuronidation reactions during phase II metabolism?
- OH
- COOH
- NH2
Which groups are rarely conjugated by glucuronidation reactions during phase II metabolism?
- NR2
- SH
- CH
What is the source for glucuronidation?
Uridine-5’diphosph-alpha-D-glucuronic acid
- UDPGA
Which enzymes are responsible for glucuronidation reactions in phase II metabolism?
UDP-glucuronosyl-transferase
- UDPGT
How is aspirin metabolised during phase II metabolism?
Glucuronidation
- ether
- ester
What does phase 2 metabolism do ?
Phase 2 metabolism links the the drug to still more polar molecules to render them even more easy to excrete
how much more ether glucuronide is formed compared to ester glucuronide during aspirin metabolism?
Twice as much
Which groups are conjugated by sulphation reactions during phase II metabolism?
- OH
- NH2
What is the source for sulphation?
3’phosphoadenosine-5’-phosphosulphate
- PAPS
Which enzyme is responsible for sulphation reactions in phase II metabolism?
Sulphotransferase
How is paracetamol metabolised during phase II metabolism?
Glucuronidation
Sulphation
What proportion are paracetamol-glucuronide and paracetamol-sulphate found in urine following phase II metabolism?
Roughly equal amounts after normal doses of paracetamol
Which groups are conjugated with glutathione (GSH)?
- Ar-X
- aryl halides
- arene oxide
- epoxide
What is glutathione (GSH)?
Tri-peptide structure consisting of
- glycine
- cysteine
- glutamic acid
How is paracetamol converted to NAPQI during phase II metabolism?
Reduction
What is produced when NAPQI is conjugated with glutathione?
Paracetamol-mercapturic acid
How is NAPQI formed?
Probable from an N-hydroxy metabolite
How is toxic NAPQI metabolised during phase II metabolism?
GSH conjugation prevents toxicity of these oxidative metabolites after normal doses
- mechanism is swamped after overdose
Which groups are conjugated by acetylation during phase II metabolism?
- OH
- NH2
Which enzyme is responsible for acetylation during phase II metabolism?
Acetyl co-enzyme A
What causes variations in some acetyl transferases?
Genetic variation
- fast and slow acetylators
- frequency varies with race
What percentage of caucasians are slow acetylators?
60%
What percentage of eskimos are fast acetylators?
95%
Which groups are conjugated by methylation during phase II metabolism?
-OH
-NH2
-SH
heterocyclic N
What is the source of methylation during phase II metabolism?
S-Adenosyl-L-methionine (SAM)
When does O-methylation occur most commonly during phase II metabolism?
With catechols with metabolism at the meta position
- COMT enzyme
How is dopamine metabolised?
Monoamine oxidase (MOA) or aldehyde dehydrogenase then COMT enzyme
OR
COMT enzyme then aldehyde dehydrogenase
Produces homovanillic acid
What is catechol?
Aromatic ring with 2 OH groups next to each other
What effect does grapefruit juice have on CYP3A4 enzymes?
Grapefruit juice inhibits the enzyme from metabolic processes -> higher levels of drug in blood -> more side effects
