Variable Drug Metabolism

Question 1

How do drug-drug interactions cause variations in drug metabolism?

Answer 1

2 drugs competing for the same enzyme

Systemic exposure to 1 or both is altered

Question 2

How do drug-diet interactions cause variations in drug metabolism?

Answer 2

Active compounds of certain foods can be P450 substrates

• grapefruit juice and CYP3A4

Question 3

How does genetic variation in gene encoding cause variations in drug metabolism?

Answer 3

Genetic variation can render an enzyme useless / cause a loss in function to the enzyme

Question 4

What other factors affect drug metabolism?

Answer 4

Underlying disease and environment / lifestyle - smoking, alcohol

Question 5

What is enzyme induction?

Answer 5

Where the enzymatic activity is increase by inducing increased hepatic protein expression - in liver

Question 6

What is auto induction?

Answer 6

Where a drug induces expression of CYP isoforms which is responsible for its own metabolism

Question 7

Give an example of auto induction.

Answer 7

Rifampicin - anti-tuberculosis drug - induces CYP3A4 hepatic expression and is also the substrate for CYP3A4

Question 8

What’s the problem with drug-drug interactions?

Answer 8

Exposure of the drug is increased, above therapeutic window and put patient at risk of toxicity / adverse drug response

Question 9

Give an example of drug-drug interactions. What’s the risk?

Answer 9

6-mercaptopurine and allopurinol

Allopurinol inhibits xanthine oxidase

Results in bone marrow toxicity - can become fatal as 6-mercaptopurine clearance is blocked

Question 10

Give an example of drug-diet interactions

Answer 10

Grapefruit juice - CYP3A4 inhibitor

Inhibits simvastatin clearance and hence becomes toxic

Question 11

What percentage of drugs does CYP2D6 metabolise in some way?

Answer 11

> 55% of all drugs

Question 12

Give an example of genetic variation

Answer 12

Ultra-rapid , extensive , intermediate and poor metaboliser

Affects the rate of metabolism of drugs - inherited from parents - by CYP2D6

Question 13

How is codeine metabolised?

Answer 13

Metabolised to morphine - 100x more potent analgesic

Dealkylatyed via CYP2D6 - oxidised in presence of NADPH

Question 14

What is irintecan? How is it metabolised?

Answer 14

Colorectal cancer drug - pro drug metabolised to SN-38

Irinotecan is hydrolysed to give SN38

Question 15

How is SN-38 metabolised?

Answer 15

Undergoes glucuronidation and is excreted in bile to form SN-38-glucuronide

Question 16

What does SN-38 toxicity result in?

Answer 16

Severe diarrhoea and neutropenia - significant decrease of white blood cells

Question 17

Give examples of toxic phase 1 metabolites

Answer 17

Epoxides
Hydroxylamines
Quinoneimines
Free radicals

Question 18

What do toxic phase 1 metabolites result in?

Answer 18

Bind to tissue macromolecules
Lipid peroxidation
Oxidative stress

Causes;
Cell damage / death
Tissue necrosis
Inflammation

Question 19

What’s the antidote to paracetamol overdose?

Answer 19

N-acetyl cysteine

Only effective up to 16hrs after initial dosing of paracetamol

Question 20

What does NAPQI - paracetamol metabolite - cause?

Answer 20

Necrosis
Liver damage
Hepatitis
DEATH

Question 21

What other pathways does paracetamol undergo to prevent NAPQI? What enzymes?

Answer 21

UDP-glucuronosyl transferase + UDPGA
-OH is glucuronidated which is more polar and more readily excretable

Sulphation via Sulphotransferase + PAPS

Question 22

How can NAPQI be metabolised?

Answer 22

Via Glutathione S-transferase

It can then be excreted

Question 23

What does N-acetylcysteine do?

Answer 23

Replenishes tripeptide needed for glutathione transferase reaction, allowing NAPQI to be metabolised and removed from the body

Question 24

What is isoniazid? What’s the issue with it?

Answer 24

Used to treat tuberculosis

Causes hepatotoxicity in 1-2% of people

Question 25

What’re slow acetylators?

Answer 25

Have lower expression of NAT enzymes in their liver hence have increased risk of hepatotoxicity

Question 26

What’re the risks slow-acetylators face with isoniazid?

Answer 26

Isoniazid - also hydrolysed to hydrazine - cannot be acetylated

Hydrazine is hepatotoxic

Question 27

What is clopidigrel?

Answer 27

Anti-platelet used to prevent heart attacks and stroke in high risk patients - thins blood

Question 28

How is clopidogrel given?

Answer 28

Given as a pro drug and is metabolised to its active thiol metabolite

Question 29

What risks surround clopidogrel?

Answer 29

Sub-optimal metabolism causes reduced efficacy and reduces effectiveness of the drug

Question 30

What enzymes metabolise clopidogrel?

Answer 30

CYP2C19 enzymes oxidise twice to form active compound

Also metabolised by hydrolysis by carboxylesterases to inactive form

Question 31

How much of clopidogrel is metabolised to form active/inactive form?

Answer 31

15% ACTIVE FORM

85% INACTIVE FORM

Question 32

What happens when CYP2C19 is inhibited in some way?

Answer 32

Clopidogrel then follows hydrolysis by carboxylesterases to form inactive compound only

Hence no response

Question 33

What % of the population cannot oxidise clopidogrel effectively?

Answer 33

3-4% means they cannot metabolise clopidogrel to its active form - to stop a heart attack/stroke