Drug Metabolism

Question 1

Why would you want a drug to be lipophilic?

Answer 1

So drugs can access tissues by crossing the lipid membranes- therapeutic effect

Question 2

Why would you want a drug to be water soluble?

Answer 2

So that it can be retained in the blood and delivered to excretion sites

Question 3

What is the aim of drug metabolism?

Answer 3

Convert lipid-soluble drugs into less lipid-soluble (water-soluble) so that it is easier to excrete

Question 4

What does the process of metabolism involve?

Answer 4

Conversion of drugs to metabolites

Question 5

What two kinds of biochemical reactions does D.M involve?

Answer 5

Phase 1 - introduce a reactive group to the drug to increase polarity
Phase 2 - add a water-soluble conjugate to the reactive group

Question 6

3 main reactions in Phase 1?

Answer 6

Oxidation - produce electrophile

Hydrolysis & reduction - produce nucleophile (-OH, -SH, -NH2)

Question 7

Function of the 3 reactions in Phase 1?

Answer 7

Oxidation/reduction - adds new functional groups (serves at a point of attachment for phase II reactions)

Hydrolysis - unmasks the functional group

Question 8

Main site and enzyme of drug metabolism in Phase 1?

Answer 8

The liver - cytochrome p450 (isoenzymes) on the SER

There are around 57 subtypes which metabolise different drugs

Question 9

Most common Phase 1 metabolism?

Answer 9

Oxidation - often starts with hydroxylation (adding an hydroxyl group)

Question 10

3 ways Phase 1 can work?

Answer 10

Active parent drug —> inert metabolite
e.g. nicotine and cocaine
Active parent drug —> active metabolite
prolongs effects as just another chemical carrying out these effects
Inactive parent drug —> active metabolite (prodrug)
e.g. codeine needs to be metabolised to morphine to work

Question 11

4 different phase 2 reactions?

Answer 11

Glutathione conjugation
Glucuronidation
Acetylation
Sulfation

Question 12

Phase 2 reaction for electrophiles?

Answer 12

Gluthathione conjugation

Conjugating agent = gluthathione

Question 13

Phase 2 reaction for nucleophile (g)?

Answer 13

Glucuronidation
Conjugating agent = UDP-glucuronic acid
Target F.G = -OH, -COOH, -NH2, -SH

Question 14

Phase 2 reaction for nucleophile (a)?

Answer 14

Acetylation
Conjugating agent = acetyl CoA
Target F.G = -OH & -NH2

Question 15

Phase 2 reaction for nucleophile (s)?

Answer 15

Sulfation
Conjugating agent = 3’-phosphoadenosine-5’-phosphosulphate
Target F.G = -OH & -NH2

Question 16

Most common Phase 2 metabolism?

Answer 16

Glucuronidation

Question 17

Property of glucuronidation?

Answer 17

Has a low affinity/high capacity

SO more likely to occur at high drug dosages

Question 18

Property of sulfation?

Answer 18

Has a high affinity/low capacity

SO more likely to occur at low drug dosages

Question 19

E.g. of paracetamol and its dosages effects on Phase 2?

Answer 19

At low dosages, sulfation occurs

At higher dosages, switches to glucuronidation

Question 20

Not all of paracetamol is metabolised by the main 2 methods - whats the 3rd method?

Answer 20

Glutathione conjugation

Question 21

How do you convert paracetamol to an electrophile?

Answer 21

Generate NAPQI - change the hydroxyl group for a double-bond O to form an electrophile

Question 22

Issue with glutathione conjugation?

Answer 22

Elecetrophiles are very reactive
If the gluthathione stores fall, high levels of reactive electrophile which can cause damage to liver, kidneys etc (happens when you OD)

Question 23

Less common Phase 2 metabolism pathways?

Answer 23

Acetylation
Methylation
Aa conjugation

Question 24

Importance of drug metabolism?

Answer 24

Biological half-life decreases
Duration of exposure reduced
Accumulation of compound in body avoided
Potency/duration of biological activity of chemical can be altered
Pharmacology/toxicology of drug can be governed by its metabolism

Question 25

Exmaple of drug that is complicated because of its metabolism?

Answer 25

Cannabis!

Very lipid-soluble and its active metabolite so can access brain tissue easily and be stored in fat tissue