Drug Metabolism

Question 1

Broadly, how does our body handle most drugs?

Answer 1

We design relatively lipid soluble drugs and the body makes them more water soluble and easier to excrete.

The process of metabolism involves the conversion of drugs into metabolites.

Question 2

What two kinds of biochemical reactions does drug metabolism involve?

Answer 2

Phase 1 reactions: the main aim is to introduce a reactive group to the drug (increase polarity)

Phase 2 reactions: the main aim is to add a water soluble conjugate to the drug.

Question 3

What is the most common phase 1 metabolism reaction?

Answer 3

oxidation (often start with hydroxylation)

Question 4

What are the 3 possible outcomes of phase 1 metabolism?

Answer 4

Active parent drug -> Inert metabolite

Active parent drug -> Active metabolite
(prolongs effects)

Inactive parent drug -> Active metabolite
(prodrug)

Question 5

Why is drug metabolism important?

Answer 5

• The biological half-life of the chemical is decreased.
• The duration of exposure is 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.

Question 6

What are possible phase 1 reactions?

Answer 6

• oxidation
• hydrolysis / reduction

Oxidation/reduction creates
new functional groups

Hydrolysis unmasks them.

Important – functional group
serves as a point of attachment
for phase II reactions

Question 7

What are the products of an oxidation as a phase 1 reaction called?

Answer 7

Electrophiles

Question 8

What are the products of a reduction / hydrolysis as a phase 1 reaction called?

Answer 8

Nucleophiles

Question 9

Which organ is mainly responsible for phase 1 metabolism?

Answer 9

The liver -> 57 variations of Cytochrome P450 in the SER of hepatocytes

these enzymes can differ amongst individuals -> people handle them differently because there are different levels of the enzyme.

Question 10

What are the 3 phase 1 reactions?

Answer 10

oxidation, reduction, hydrolysis

Question 11

What are the possible phase 2 reactions?

Answer 11

• glutathione conjugation
• glucorinidation
• acetylation
• salvation

Question 12

What is the most common phase 2 reaction?

Answer 12

Glucuronidation

Question 13

When does Glucuronidation occur as a phase 2 reaction?

Answer 13

Glucuronidation is low affinity/high capacity – more likely to occur at high drug dosages.

Question 14

When does salvation occur as a phase 2 reaction?

Answer 14

Sulfation is high affinity/low capacity – more likely to occur at low drug dosages

Question 15

Glutathione conjugation

Answer 15

Drug needs to be electrophilic to be conjugated or biotransformed to an
electrophilic conjugate.

Question 16

What is the underlying problem with paracetamol overdose?

Answer 16

Glutathione stores are overwhelmed, there are large amounts of the very reactive electrophile

Question 17

What are some less common phase 2 reactions?

Answer 17

acetylation, methylation, amino acid conjugation

Question 18

How is Paracetamol metabolised?

Answer 18

40-60% Sulfation
20-30% Glucoronidation
Remaining 10% is oxidised to NAPQI and glutathione conjugation can occur (given there are enough glutathione stores, overdose: glutathione stores are overwhelmed)

Question 19

What 2 reactions are possible with amino acid conjugation as a phase 2 reaction?

Answer 19

• with carboxylic acid group of AA

- with amino group of AA