Metabolism Flashcards
Which liver enzyme metabolizes 1/2 of the drugs used today?
CYP 450 family… CYP34A is involved the most
Introduction of OH group at a saturated carbon atom (mechanism steps)
- Abstraction of a hydrogen atom – From WEAK C-H bond (forms a table carbon centered radical)
- Reaction with molecular oxygen to form a hydroperoxy radial
- Abstraction of a hydogen atom from ANOTHER molecule giving a hydroperoxide
- Reduction of the hydroperoxide to an ALCOHOL
Intro of OH group at saturated (sp3)… key part?
- active site in cytochrome enzyme – Fe+2
- can from Fe-hydro-peroxide + carbon centered radical which react together to form alcohol and Fe(O) species.
Stability of types of structures
Allylic and benzylic radicals are as or more stable than tertiary radicals resonance stabilization
Why are R2N-CH3 and Ar-O-CH3 favourable?
They have a weak C-H bond which makes abstraction much easier
Intro of OH group into aromatic rings
- Formation of an epoxide followed by rearrangement
aliphatic
- SINGLE (alkanes)
- rings without double bonds - not aromatic
Why is a different mechanism observed in aliphatic systems?
- Aromatic and alkenes have higher bond strength than aliphatic compounds
- aromatic+alkenes are much less stable
When is abstractation hard to do?
Strong C-H bond such as in aromatic rings and double bonds makes it difficult for the enzyme to perfrom an abstractation of a hydrogen
Effects of substituents on aromatic hydroxylation (nucleophile)
- Substituent that is electron donating will increase reactivity
- Substituent that is electron withdrawing will decrease reactivity
How can you slow down metabolism of an aromatic drug?
- add an EWG (F or Cl) which;
1. slows down the rate of metabolism
2. Increase half life
3. increases lipophilicity aka log P(makes it hydrophobic)
What kind of rings are more stable than a benzene ring?
- Electron poor aromatic rings tend to be metabolically more stable than a benzene ring
- Low electron density – high metabolic stability (decreases rate)
- high electron density – low metabolic stability (increases rate)
In terms of stability, what increases the rate of metabolism?
- low stability = low rate of metabolism (aromatics)
- high stability = high rate of metabolism (epoxide formation rate is also high) (alkanes)
3 things that need to be taken into consideration (drug to drug interaction)
- Metabolism
- degree of inhibition
- therapeutic index
Therapeutic index formula
Toxic dosage for 50% (TD50)/Therapeutic dosage for 50%(ED50)
