Drug Metabolism Pt 7: Notes II Flashcards
In ____, alcohol dehydrogenase can take CH2OH -> CHO.
Aldehydedehydrogenase can take CHO -> COOH.
These reactions are technically reversible, but it is _____
As the amount of –COOH reduces, the reaction goes towards the
right converting _____
- primary alcohols
- driven by excretion.
- CH2OH to CHO and COOH.
Alcohol oxidation can be done in secondary alcohols too, but it usually is not favored.
This is because alcohol is a H bond donor and acceptor, while ketone is only a H bond acceptor. This makes alcohols more polar and thus readily excreted.
A secondary alcohol may go through _____
Phase 2 reaction or be excreted as it is.
E.g. of alcohol oxidation importance
o Seldane is a non sedative antihistamine, because the aliphatic carbon
CH3 -> CH2OH (BY P450) -> CHO (ALCOHOL DH) -> COOH (BYALDEHYDE DH).
The COOH form of the drug is too polar to go to the CNS so it is non sedating.
o The problem arises if the first pass metabolism of seldane doesn’t occur so that the aliphatic carbon doesn’t get converted to the alcohol form. This can lead to the accumulation of the drug, which prolongs the UT interval of the drug, cause
arythmias and cardiotoxicity.
o To fix this problem, the aliphatic carbon is replaced by a –COOH group so we don’t have to worry about it.
Ketone reductions
- Typically, aldehydes don’t get reduced- they get oxidized to carboxylic acids by aldehyde dehydrogenase.
- Ketones get reduced to secondary alcohol by keto-reductase.
- NADH -> ____during ketone reduction
NAD
Ketone reductions
The metabolites (COOH form of the drug) is often active too because we don’t change the structure of the drug too dramatically by going from ketone to carboxylic acid. • However, we still change stereochemistry of the drug depending on from which side the H attacks the carbonyl group. • The stereochemistry \_\_\_\_\_\_.
dictates if a drug would be excreted
Hydrolytic reactions: ester hydrolysis
RCOOR -> RCOOH + HOR
- The reaction happens because water is activated and alcohol is a good leaving group
- Enzymes that perform this reaction are called esterases and it is synthesized in liver, blood, kidneys, intestine.
Uses of hydrolytic reactions:
o Unmask polar functional groups to aid excretion and conjugation.
o Terminate drug action- mostly for this use!
o Sometimes may yield active metabolites.
o Very facile: works with a simple mechanism easily
o Helps prevent acid catalyzed decarboxylation to prevent inactivation of drug.
Ester hydrolysis can be slowed down by
stearic hindrance
Amide hydrolysis
• RCONHR -> RCOOH + NH2R
• Amidases are found in the liver.
• The reaction unmasks polar functional groups and ____
usually terminates drug action
• Amide hydrolysis is less facile (happen less readily) than ester hydrolysis because
o They are more esterases in the body than amidases
o Amides have resonance that stabilize the structure.
• Slower hydrolysis helps increase the half life of the drug