Drug Metabolism

Question 1

What does metabolism tend to do to a drug?

Answer 1

Metabolism tends to eliminate or reduce the pharmacological and toxicological activity of a drug.
It makes the drug more polar and soluble so that it can more easily be excreted.

Question 2

What is hepatic first pass metabolism?

Answer 2

Metabolic conversion of the drug into something that is different before the drug enters the circulation.

Drugs absorbed from GI tract will have to go through the liver first via portal System. A proportion of the drug will be metabolised in the liver during this process.

note that first pass metabolism refers to multiple organs that could metabolise the drug before it enters systemic circulation, but hepatic refers specifically to liver

Question 3

What effect does extensive first pass metabolism have on bioavailability?

Answer 3

Extensive first pass metabolism -> low bioavailability

Question 4

How can you avoid hepatic first pass metabolism?

Answer 4

Gibing a drug intravenously

Question 5

What are the three types of reaction that fall under phase I reactions?

Answer 5

Oxidation
Reduction
Hydrolysis

Question 6

What is the purpose of Phase I metabolism?

Answer 6

Oxidation and reduction- creates new functional groups
Hydrolysis- unmasks functional groups

to introduce a ‘door handle’ ie the functional group. This functional group is then used for attachment of a polar group in phase 2 reactions

Question 7

How do phase I reactions affect polarity of the drug?

Answer 7

They have little effect on the polarity of a drug

Question 8

What enzyme system is extremely important to drug metabolism?Where are these enzymes found?

Answer 8

Cytochrome P450

It is a family of 57 enzymes that are mainly found in the liver and they are capable of metabolising MOST xenobiotics

They are involved mainly in PHASE 1 OXIDATION REACTIONS

Question 9

What are the substrates and products of the Cytochrome P450mediated oxidation reaction?

Answer 9

Substrates = drug, NADPH, oxygen (O2), protons (H+) 
Products = hydroxylated drug, NADP+, water

RH(drug) + NADPH + O2 + H+
–> ROH (hydroxylated drug) + NADP+ + H2O

Question 10

What do P450 enzymes have in their catalytic site?

Answer 10

They all have a porphyrin ring and an iron group (Fe3+)

this is why he put P450-Fe3+ on slide 10

Question 11

Describe the oxidation cycle of Cytochrome P450.

Answer 11

1. The drug binds to the Fe3+ in the catalytic site of CYP450
2. An electron is fed in from NADPH, which is picked up by the Fe3+ making it Fe2+
3. Then molecular oxygen binds to the catalytic site and Fe2+ loses its electron to become Fe3+ again, and oxygen picks up the extra electron and becomes unstable
4. Then a second electron is donated by NADPH, which, again, reduces Fe3+ to Fe2+ Fe2+ then donates this electron to the already unstable oxygen to make it even more unstable
5. Then we get conversion of the drug to the hydroxylated derivative and we lose reactive oxygen as water after the oxygen reacts with 2 protons to form H2O.
6. The drug is released and P450, along with its Fe3+, is ready to undergo another cycle

THE NET RESULT:
Drug is hydroxylated by P450. Oxidation reactions generally start with a hydroxylation step that is catalysed by the P450 system

Question 12

What is N-demethylation? What does this reaction produce?

Answer 12

This is the oxidation of a methyl group that is bound to a nitrogen
It produces formaldehyde (HCHO)

Question 13

What does N-demethylation do to a drug?

Answer 13

It is an effective way of removing the pharmacological activity of a drug

Question 14

What is O-demethylation?

Answer 14

Oxidative attack of P450 on a methyl group attached to oxygen
This converts oxygen to the hydroxyl group and release formaldehyde (HCHO)

Question 15

What is N-oxidation? Describe the type of bond formed.

Answer 15

It is the oxidation of the nitrogen group itself
Nitrogen has two free electrons that can form a dative bond with oxygen
This generates an amino oxide

Question 16

Which enzyme catalyses the N-oxidation reaction?

Answer 16

Flavin containing monooxygenase

Question 17

Describe a condition involving this enzyme?

Answer 17

Flavin containing monooxygenase deficiency (fish odour syndrome)
Trimethylamine is produced in the GI tract as a product of proteinmetabolism Trimethylamine is foul smelling but is converted by flavin containing monooxygenase in the liver to trimethylamine N-oxide, which is odourless and can be excreted in the urine
People without flavin containing monooxygenase are unable to do this conversion so they produce trimethylamine that they can’t excrete so they end up smelling terrible

Question 18

Describe alcohol oxidation.

Answer 18

Alcohol is first converted to acetaldehyde by alcohol dehydrogenase It is then converted from acetaldehyde to acetic acid, which is excreted

Question 19

Where, within the ultrastructure of a cell, are flavin containing monooxygenase and cytochrome P450 enzymes found?

Answer 19

Endoplasmic reticulum

Question 20

Where, within the ultrastructure of a cell, is alcohol dehydrogenase found?

Answer 20

Cytoplasm

Question 21

Where do reduction reactions tend to take place within the body and why?

Answer 21

GI tract because this is a low oxygen environment

Most reductases are bacterial enzymes that are colonising our gut, which is why these tend to happen in the GI tract

Question 22

State two types of hydrolysis enzymes.

Answer 22

Esterases and Amidases

Question 23

What are the six types of phase II reactions?

Answer 23

Glucuronidation 
Acetylation 
Sulphation 
Methylation 
Amino Acid Conjugation 
Glutathione Conjugation

Question 24

State each of the enzymes that are responsible for carrying outthese six types of phase II reactions.

Answer 24

Glucuronyl Transferase 
Acetyl Transferase 
Sulphotransferase 
Methyl Transferase 
Acyl Transferase  
Glutathione S-Transferase

Question 25

What effect do phase II reactions have on the drugs?

Answer 25

They make drugs more polar and water-soluble (less lipid-soluble) so that they can be excreted more easily

Question 26

What are some features of conjugating agents?

Answer 26

Large
Polar
Endogenous

Question 27

What is the most common type of phase II reaction?

Answer 27

Glucuronidation (addition of a sugar to a molecule)

Question 28

What is the importance of glutathione conjugation?

Answer 28

Glutathione is conjugated with electrophiles so that they can be excreted
Electrophiles are damaging species that are often generated during metabolism – they must be removed because they can cause DNA and protein damage (DNA= most electron dense thing in the body)

Question 29

State a conjugating agent that is used for glucuronidation.

Answer 29

UDPGA

Question 30

State an important property of the conjugates formed fromglucuronidation and its impact on its excretion.

Answer 30

They are large molecular weight products so it has a problem withglomerular filtration
High molecular weight molecules are often excreted in the bile

Question 31

What is the conjugating agent in acetylation and what is the product?

Answer 31

Acetyl CoA

The product is the acetylated derivative of the drug and CoA (CoA then goes into intermediary metabolism)

Question 32

What is the conjugating agent/high energy intermediate for methylation?

Answer 32

S-adenosyl methionine

Question 33

What effect does methylation have on polarity?

Answer 33

It DECREASES polarity

Question 34

What is the conjugating agent used in sulphation?

Answer 34

PAPS – 3’-phosphoadenosine-5’-phosphosulphate

Question 35

What are the properties of the derivative formed in sulphation?

Answer 35

The product is the sulphuric acid derivative of the drug

This is very polar and water-soluble

Question 36

What type of molecule is glutathione?

Answer 36

Tripeptide consisting of: Glycine
Glutamine
Cysteine

Question 37

What effect does drug metabolism have on biological half-life, duration of exposure and accumulation of drugs in the body?

Answer 37

Decreases biological half-life
Decreases duration of exposure
Avoids accumulation of drugs in the body