Metabolic Changes of Drugs and Related Organic Compounds Flashcards Preview

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Flashcards in Metabolic Changes of Drugs and Related Organic Compounds Deck (34):

2 ways that body deals with foreign drugs

1. Try to clear them from the body
2. Try to deactivate them (which occasionally actually makes it more active)


2 pathways of drug metabolism

1. 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
Alkylating drugs to form inactive metabolites


Where the majority of xenobiotic metabolism occurs



Another common place for metabolism

Intestinal mucosa (small intestine; capable of reducing certain drugs)


Most common phase I processes



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
1. Fe+3 is reduced to Fe+2
2. O2 binds Fe+2, making O2- (superoxide)
3. 1 O of O2- is turned into H2O, leaving the other to become an activated oxygen species (electrophilic)
4. 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)
1. Epoxide forms at aromatic ring
2. Epoxide resolves into zwitterionic species (negative charge on O and positive charge on neighboring carbon)
3. Formation of ketone
4. 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:
1. 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)
2. 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

1. S-dealkylation (via alpha-hydroxylation)
2. Desulfuration (turning C-S double bond to C-O double bond; mechanism poorly understood)
3. 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)



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