Drug metabolism

Question 1

What is phase 1 metabolism of drugs do in general?

Answer 1

Oxidation and reduction add a new functional group and hydrolysis unmasks them.

Question 2

What do phase 1 metabolic reactions often make

Answer 2

Inactive chemicals, or prodrugs, or toxic metabolites

Question 3

What different reactions are in phase 1 metabolic reactions?

Answer 3

Oxidation
Reduction
Hydrolysis

Question 4

What does the functional group added in phase 1 metabolic reactions do?

Answer 4

Act as an attachment point for phase 2 reactions

Question 5

What is the ‘hepatic first pass’?

Answer 5

All drug dose absorbed from the GI tract is first delivered to the liver by the portal vein. A fraction of the drug can then be metabolised in the liver before it reaches the systemic circulation so oral bioavailability of the drug is lower

Question 6

Are xenobiotics usually lipophillic or lipophobic?

Answer 6

Lipophillic

Question 7

What does metabolism tend to do? How?

Answer 7

Reduce or eliminate pharmacological activity by converting lipophilic chemicals to polar derivatives that are readily excreted

Question 8

What happens to polarity of drugs after phase 1

Answer 8

It doesn’t change much after phase 1

Question 9

What is the name of the set of enzymes that are important in phase 1

Answer 9

Cytochrome P450 Enzymes

Question 10

Where are CYP450 enzymes predominantely found?

Answer 10

Liver

Question 11

How many isoenzyme varieties of CYP450 are there?

Answer 11

57 Varieties

Question 12

How do the CYP450 enzymes do their thing? What are the steps?

Answer 12

1. Substrate binds to the gerric on the P450 enzyme
2. Electron reduces the ferric
3. Oxygen binds to P450 and ferrous is formed in the process
4. A further reduction occurs to form a negatively charged oxygen and a ferric again (RDS)
5. Ferric donates an electron to oxygen to form a very polar molecule
6. O2 is then cleaved which reacts with 2 protons to form water
7. Drug is then released from the system in a hydrolysed form

Question 13

What step do oxidation reactions catalysed by P450 system start with (generally)

Answer 13

Hydroxylation step

Question 14

What is the rate limiting step of the P450 enzyme reactions?

Answer 14

Reduction making a negatively charged oxygen and ferric

Question 15

What is an aliphatic?

Answer 15

Straight chains of carbon atoms

Question 16

What is aromatic?

Answer 16

Ring systems of carbon atoms

Question 17

What happens in a hydroxyl oxidative reaction in phase 1?

Answer 17

1. First reaction inactivates the pentobarbitone drug by adding an OH to the penultimate carbon
2. second reaction is the activation of paracetamol from the prodrug Acetanilide by adding an OH group to the ring

Question 18

What happens in a demethylation oxidative reaction in phase 1?

Answer 18

Methyl group removed from nitrogen or the oxygen depending on the drug

Question 19

What is important to consider in a person when working out the dose of morphine to give someone?

Answer 19

Codeine is a prodrug that is activated by P450 enzymes and the dose would depend on how effective someones P450 enzymes are

Question 20

What happens in a n-oxidative or alcohol oxidation reaction in phase 1?

Answer 20

Nitrogen becomes oxidised and forms a dative covalent bond with the oxygen atom (creates a very polar thus lipophilic molecule that can be excreted)
Using alcohol dehydrogenase (zero order enzyme), ethanol oxidised to acetaldehyde

Question 21

What happens in reduction or hydrolysis reactions in phase 1?

Answer 21

Reduction breaks the molecule by adding electrons into the system
Hydrolysis then also severs the molecule into two

Question 22

What is the most common reaction in phase 1?

Answer 22

Oxidation

Question 23

What reactions take place in phase 2 metabolism?

Answer 23

Glucuronidation
Acetylation
Amino acid conjugation
Sulphation
Methylation
Glutathione conjugation

Question 24

What is special about conjugates?

Answer 24

They are almost always pharmacologically inactive. They are less lipid soluble and easier to excrete

Question 25

What is a conjugating agent?

Answer 25

An agent that attaches a polar group onto the molecule in question

Question 26

What is the conjugating agent and target functional group for glycuronidation?
What is formed?

Answer 26

UDP-glucuronic acid
-OH, -COOH, -NH2, -SH
A high energy phosphate compound is formed

Question 27

What is the conjugating agent and target functional group for acetylation?

Answer 27

Acetyl CoA

-OH, -NH2

Question 28

What is the conjugating agent and target functional group for amino acid conjugation?

Answer 28

Glycine, Glutamine

-COOH

Question 29

What is the conjugating agent and target functional group for methylation?

Answer 29

S-adenosyl-methionine

-OH, -NH2

Question 30

What is the conjugating agent and target functional group for sulphation?

Answer 30

3’-phosphoadenosine-5’-phosphosulphate

-OH, -NH2

Question 31

What is the conjugating agent and target functional group for glutathione conjugation?

Answer 31

Glutathione

Electrophiles

Question 32

Where is the acetyl group or methyl group transferred to in acetylation/methylation?

Answer 32

an electron rich atom

Question 33

What catalyses the transfer of sulfates to substrates in sulphation?

Answer 33

Sulphotransferases

Question 34

What is glutathioneused for in conjugation with glutathione?

Answer 34

To remove potentially toxic compounds

Question 35

Why is drug metabolism important?

Answer 35

Biological half life reduced
Duration of exposure reduced
Accumulation of the compound in the body is avoided
Potency/duration of the biological activity of the chemical can be altered
The pharmacology/toxicology of the drug can be governed by its metabolism