Metabolic Changes of Drugs and Related Organic Compounds

Question 1

2 ways that body deals with foreign drugs

Answer 1

1. Try to clear them from the body

2. Try to deactivate them (which occasionally actually makes it more active)

Question 2

2 pathways of drug metabolism

Answer 2

1. Phase I reactions (functionalization)

2. Phase II reactions (conjugation)

Question 3

Phase I reactions (functionalization)

Answer 3

Introducing polar functionalities to increase water solubility of a drug
Oxidations, reductions, or hydrolytic reactions

Question 4

Phase II reactions (conjugation)

Answer 4

Attaching small, polar molecules to existing drugs to form water-soluble conjugated products
or
Alkylating drugs to form inactive metabolites

Question 5

Where the majority of xenobiotic metabolism occurs

Answer 5

Liver

Question 6

Another common place for metabolism

Answer 6

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

Question 7

Most common phase I processes

Answer 7

Oxidations

Question 8

Cytochrome P-450s

Answer 8

Family of mixed-function oxidases that aid in phase I processes
Highly abundant in endoplasmic reticulum of liver cells

Question 9

Mechanism of cytochrome P-450s

Answer 9

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

Question 10

Aromatic hydroxylation

Answer 10

Conversion of aromatic compounds to phenolic metabolites
Proceeds through an epoxide intermediate (electrophilic aromatic substitution)
Usually, hydroxylation occurs at para position
Usually stereospecific

Question 11

NIH shift

Answer 11

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

Question 12

Benzylic/allylic oxidation

Answer 12

Carbon atoms at benzylic or allylic positions are susceptible to oxidation to their corresponding benzylic/allylic alcohol

Question 13

Oxidation of aliphatic carbons

Answer 13

Carbon atoms at terminal and almost terminal positions are subject to oxidation

Question 14

Heteroatom (O,N,S) oxidations

Answer 14

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

Question 15

Oxidation of tertiary amines: oxidative N-dealkylations

Answer 15

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

Question 16

Oxidation of tertiary amines: conversion of alicyclic tertiary amines to lactams

Answer 16

Adding -OH to carbon atom alpha to nitrogen

Secondary alcohol is converted to ketone

Question 17

Oxidation of tertiary amines: direct N-oxidation

Answer 17

Often competes with reduction of N-oxides back to parent tertiary amine

Question 18

Oxidation of secondary amines

Answer 18

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)

Question 19

Oxidation of primary amines

Answer 19

If possible, susceptible to oxidative deamination

If no alpha protons are available, then they are metabolized via direct N-oxidation

Question 20

Oxidation of ethers

Answer 20

Usually undergo oxidative dealkylation to yield an alcohol/phenol and a ketone/aldehyde

Question 21

3 ways that carbon-sulfur systems are oxidized

Answer 21

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

Question 22

How alcohols are metabolized

Answer 22

Either conjugated via phase II reactions or oxidized via soluble alcohol dehydrogenases

Question 23

Functional groups that are metabolized via reduction

Answer 23

Carbonyls, nitro groups, azo groups

Question 24

Metabolism of aldehydes

Answer 24

Rarely reduced

Mostly oxidized to -CO2H

Question 25

Reduction of nitro groups

Answer 25

Nitro groups are reduced to primary amines (-NO2 to -NO to -NHOH to -NH2)

Question 26

Reduction of azo groups

Answer 26

Azo groups are reduced to primary or secondary amines (-N=N- to -NH-NH- to 2 -NH2s)

Question 27

Functional groups that are prone to metabolic hydrolysis

Answer 27

Esters and amides (but esters are more readily hydrolyzed)

Question 28

Beta-glucuronidation

Answer 28

Most common type of phase II conjugation pathway

Utilizes UDP-alpha-glucuronic acid to react with -OH groups and some -NH2 groups

Question 29

Synthesis of UDP-alpha-glucuronic acid

Answer 29

Alpha-D-glucose-1-phosphate -> UDP-glucose -> double oxidation to UDP-alpha-glucuronic acid

Question 30

Sulfate conjugation

Answer 30

Primarily occurs with phenols

Common route in infants, less so in adults

Question 31

Amino acid conjugation

Answer 31

Usually glycine and glutamine
Main substrates are carboxylic acids: carboxylic acid is first activated as a CoA-thioester
Products are N-acyl amino acids

Question 32

Glutathione conjugation

Answer 32

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

Question 33

Phase II acetylation

Answer 33

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)

Question 34

Phase II methylation

Answer 34

Relatively minor pathway for xenobiotic metabolism
Methylated products are inactive
Catalyzed by O-, N-, and S-methyltransferases