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)
Therapeutic index
- Ideally it is a large number
- If it is less than 5 (narrow window + small margin of error for safety)
Why do some cancer cells have small TI’s?
- This is because they are trying to be toxic to most cells (aka cancer) the drug has to be toxic but safe ish
Digoxin
Small TI
Acetominophen
Large TI
First pass metabolism
- the concentration of a drug is greatly reduced before it reaches the systemic circulation
Oral administration
- Drugs absorbed thru intestine + go to liver
- oxidative metabolisms occur in the gut
- can be avoided by releasing drug into blood stream before it can be metabolized by liver enzymes
Different modes of administration
- Oral – most common, reasonable compliance
- Intravenous injection typical of many anti-cancer drugs, often problems with formulations
- Intramuscular injection –most vaccines, acid sensitive penillins
- Sublingual - angia drugs (ex. nitroglycerin)
[Rapid absorption into the blood, rapid action] - Inhalation- asthma drug – “puffer”
- Transdermal- hormones, nicotine patch
7Rectal suppositories –aspirin
What can you do for a drug to stay in body longer?
- adjust dosage = less rapid metabolism
2. avoid stomach where it is acidic and destroys compounds
