Metabolic Changes of Drugs and Related Organic Compounds Flashcards
2 ways that body deals with foreign drugs
- Try to clear them from the body
2. Try to deactivate them (which occasionally actually makes it more active)
2 pathways of drug metabolism
- Phase I reactions (functionalization)
2. Phase II reactions (conjugation)
Phase I reactions (functionalization)
Introducing polar functionalities to increase water solubility of a drug
Oxidations, reductions, or hydrolytic reactions
Phase II reactions (conjugation)
Attaching small, polar molecules to existing drugs to form water-soluble conjugated products
or
Alkylating drugs to form inactive metabolites
Where the majority of xenobiotic metabolism occurs
Liver
Another common place for metabolism
Intestinal mucosa (small intestine; capable of reducing certain drugs)
Most common phase I processes
Oxidations
Cytochrome P-450s
Family of mixed-function oxidases that aid in phase I processes
Highly abundant in endoplasmic reticulum of liver cells
Mechanism of cytochrome P-450s
Metalloproteins, containing a heme ring with a Fe+2/Fe+3 atom
- Fe+3 is reduced to Fe+2
- O2 binds Fe+2, making O2- (superoxide)
- 1 O of O2- is turned into H2O, leaving the other to become an activated oxygen species (electrophilic)
- Activated oxygen can oxidize functional groups
Aromatic hydroxylation
Conversion of aromatic compounds to phenolic metabolites
Proceeds through an epoxide intermediate (electrophilic aromatic substitution)
Usually, hydroxylation occurs at para position
Usually stereospecific
NIH shift
1,2-shift of H (H goes from 1 position to 2 position)
- Epoxide forms at aromatic ring
- Epoxide resolves into zwitterionic species (negative charge on O and positive charge on neighboring carbon)
- Formation of ketone
- Ketone tautomerizes to form hydroxylated aromatic ring
Benzylic/allylic oxidation
Carbon atoms at benzylic or allylic positions are susceptible to oxidation to their corresponding benzylic/allylic alcohol
Oxidation of aliphatic carbons
Carbon atoms at terminal and almost terminal positions are subject to oxidation
Heteroatom (O,N,S) oxidations
2 classes:
- Hydroxylation of carbon atoms alpha to heteroatom (adding -OH to alpha carbon ends up creating ketone of alpha carbon and heteroatom with one extra H bound to it)
- Hydroxylation of the N or S heteroatom itself
Oxidation of tertiary amines: oxidative N-dealkylations
Adding -OH to carbon atom alpha to nitrogen
In the end, yields ketone of alpha carbon and nitrogen with 1 extra H bound to it
Oxidation of tertiary amines: conversion of alicyclic tertiary amines to lactams
Adding -OH to carbon atom alpha to nitrogen
Secondary alcohol is converted to ketone
Oxidation of tertiary amines: direct N-oxidation
Often competes with reduction of N-oxides back to parent tertiary amine
Oxidation of secondary amines
Like tertiary amines, susceptible to N-dealkylations and N-oxidations (result in hydroxylamines, which can be further oxidized to nitrones)
Also undergo oxidative deaminations (similar to N-dealklyation, but occurring on larger alkyl groups)
Oxidation of primary amines
If possible, susceptible to oxidative deamination
If no alpha protons are available, then they are metabolized via direct N-oxidation
Oxidation of ethers
Usually undergo oxidative dealkylation to yield an alcohol/phenol and a ketone/aldehyde
3 ways that carbon-sulfur systems are oxidized
- S-dealkylation (via alpha-hydroxylation)
- Desulfuration (turning C-S double bond to C-O double bond; mechanism poorly understood)
- S-oxidation
How alcohols are metabolized
Either conjugated via phase II reactions or oxidized via soluble alcohol dehydrogenases
Functional groups that are metabolized via reduction
Carbonyls, nitro groups, azo groups
Metabolism of aldehydes
Rarely reduced
Mostly oxidized to -CO2H
Reduction of nitro groups
Nitro groups are reduced to primary amines (-NO2 to -NO to -NHOH to -NH2)
Reduction of azo groups
Azo groups are reduced to primary or secondary amines (-N=N- to -NH-NH- to 2 -NH2s)
Functional groups that are prone to metabolic hydrolysis
Esters and amides (but esters are more readily hydrolyzed)
Beta-glucuronidation
Most common type of phase II conjugation pathway
Utilizes UDP-alpha-glucuronic acid to react with -OH groups and some -NH2 groups
Synthesis of UDP-alpha-glucuronic acid
Alpha-D-glucose-1-phosphate -> UDP-glucose -> double oxidation to UDP-alpha-glucuronic acid
Sulfate conjugation
Primarily occurs with phenols
Common route in infants, less so in adults
Amino acid conjugation
Usually glycine and glutamine
Main substrates are carboxylic acids: carboxylic acid is first activated as a CoA-thioester
Products are N-acyl amino acids
Glutathione conjugation
Common phase II pathway for electrophilic xenobiotics
Conjugation catalyzed by glutathione-S-transferase
Initial conjugation products are often further metabolized via the mercapturic acid pathway
Phase II acetylation
Important metabolic route for xenobiotics containing a primary amine
Acetyl CoA: acetylating agent
Catalyzed by N-acetyltransferases
Acetylation inactivates
Decreases water solubility of an amine (usually linked to other phase I or II events to offset this effect)
Phase II methylation
Relatively minor pathway for xenobiotic metabolism
Methylated products are inactive
Catalyzed by O-, N-, and S-methyltransferases
