CYP450

Question 1

Substrate, Inducer or Inhibitor: Rifampicin

Answer 1

CYP450 Inducer

Question 2

Substrate, Inducer or Inhibitor: Statins

Answer 2

CYP450 Substrate

Question 3

What is an Inducer?

Answer 3

Inducers increase the expression level of CYP450 enzymes resulting in increased metabolism of drugs and subsequently reducing the therapeutic concentration.

Therefore, potential changes in drug concentration may cause treatment failure. The effects usually develop over several days and may be slow to resolve depending on the half-life of the inducer.

Question 4

What is a substrate?

Answer 4

Enzyme substrates are drugs or other substances that bind to and are metabolised by the CYP450 enzymes

Question 5

What is an inhibitor?

Answer 5

Inhibitors prevent the CYP450 enzymes from working or reduce the rate of an enzyme-catalysed reaction. Consequently, this decreases drug metabolism in the body and increases the potential for toxicity. The effect often occurs quickly and is dose related.

Question 6

Substrate, Inducer or Inhibitor: Theophylline

Answer 6

CYP450 Substrate

Question 7

Substrate, Inducer or Inhibitor: Phenytoin

Answer 7

CYP450 Substrate

Question 8

Substrate, Inducer or Inhibitor: Warfarin

Answer 8

CYP450 Substrate

Question 9

Substrate, Inducer or Inhibitor: Selective serotonin reuptake inhibitors (SSRI): sertraline, citalopram, fluoxetine

Answer 9

CYP450 Substrate

Question 10

Substrate, Inducer or Inhibitor: Amitriptyline

Answer 10

CYP450 Substrate

Question 11

Substrate, Inducer or Inhibitor: Codeine

Answer 11

CYP450 Substrate

Question 12

Substrate, Inducer or Inhibitor: Caffeine

Answer 12

CYP450 Substrate

Question 13

Substrate, Inducer or Inhibitor: Nicotine/ Cigarette smoke

Answer 13

CYP450 Inducer

Question 14

Substrate, Inducer or Inhibitor: Antibiotics: rifampicin, griseofulvin

Answer 14

CYP450 Inducer

Question 15

Substrate, Inducer or Inhibitor: Steroids: dexamethasone, prednisolone, glucocorticoids

Answer 15

CYP450 Inducer

Question 16

Substrate, Inducer or Inhibitor: Anticonvulsants: phenytoin, carbamazepine, phenobarbitone

Answer 16

CYP450 Inducer

Question 17

Substrate, Inducer or Inhibitor: Alcohol

Answer 17

CYP450 Inducer

Question 18

Substrate, Inducer or Inhibitor: St John’s Wort

Answer 18

CYP450 Inducer

Question 19

Substrate, Inducer or Inhibitor: Antibiotics: sulfonamides, metronidazole, ciprofloxacin, chloramphenicol, macrolides, isoniazid

Answer 19

CYP450 Inhibitor

Question 20

Substrate, Inducer or Inhibitor: Cimetidine

Answer 20

CYP450 Inhibitor

Question 21

Substrate, Inducer or Inhibitor: Omeprazole

Answer 21

CYP450 Inhibitor

Question 22

Substrate, Inducer or Inhibitor: Sodium valproate

Answer 22

CYP450 Inhibitor

Question 23

Substrate, Inducer or Inhibitor: Azoles: ketoconazole, fluconazole

Answer 23

CYP450 Inhibitor

Question 24

Substrate, Inducer or Inhibitor: Grapefruit

Answer 24

CYP450 Inhibitor

Question 25

What should you consider before prescribing oral contraceptives for patients taking St John’s wort?

Answer 25

St John’s wort is a CYP450 3A4 and 3A5 enzymes inducer. It increases the metabolism and clearance of oral contraceptive pills such as levonorgestrel, norethisterone, ethinylestradiol and desogestrel from the body. As a result, patients may experience breakthrough bleeding and potential contraceptive failure.

St John’s wort should not be taken concurrently with oral contraceptive pills or patients should use alternative methods such as barrier methods, depots and intrauterine devices (IUD).

For patients who require emergency contraception, a copper IUD is preferred over levonorgestrel. However, in cases where a contraindication arises for a copper IUD, 3 mg of levonorgestrel should be given as a single dose during and within 28 days after stopping St John’s wort

Question 26

What should you consider when prescribing miconazole (for oral thrush) for patients taking warfarin

Answer 26

Miconazole is a CYP450 2C9 enzyme inhibitor. It inhibits the metabolism and clearance of warfarin, subsequently causing a rapid and extensive increase in warfarin concentration in the body. As a result, the anticoagulant effect of warfarin is increased, measured by an increase in the international normalised ratio (INR).

Miconazole should not be prescribed concurrently with warfarin. If necessary, monitor INR and reduce a patient’s warfarin dose accordingly. Patients should be advised to seek immediate medical attention if they experience any signs of bleeding, which include unexplained bruising, nose bleeds, or blood in their urine

Question 27

What is CYP450?

Answer 27

Cytochrome P450 (CYP450) are a group of enzymes encoded by the P450 genes and responsible for the metabolism of most drugs seen in clinical practice.

90% of drugs are metabolised by CYP3A5, CYP3A4, CYP2D6, CYP2C19, CYP2C9 and CYP1A2.
CYP3A4 and CYP2D6 are the most important of these enzymes

Question 28

What are poor metabolisers?

Answer 28

Poor metabolisers (PM) are characterised by the inability to metabolise drugs via the CYP2D6 metabolic pathway, resulting in an increased risk of adverse effects and toxicity.

The reverse applies to prodrugs. Poor metabolisers fail to convert the prodrug into its active form leading to a lack of therapeutic response.

PM phenotype affects up to 10% of Caucasians and 30% of the Chinese population.

Question 29

What are ultrarapid metabolisers?

Answer 29

Ultrarapid metabolisers metabolise the drug rapidly, resulting in a lack of therapeutic response in these individuals.

The reverse applies to prodrugs. Ultrarapid metabolisers rapidly convert the prodrug to its active form, causing potential toxicity.

Ultrarapid metaboliser phenotypes are most prevalent in the North African, Ethiopian and Arab populations, affecting 16% – 28% of the populations. In the rest of the world, the prevalence of ultrarapid metaboliser phenotypes is estimated to be 1% in the Chinese, Japanese and Hispanic populations and 5.5% in Western Europe.

Question 30

What are the 3 functions of CYPs?

Answer 30

• Convert a toxic metabolite into a non-toxic metabolite
• Convert a pro-drug into an active drug
• Convert an active drug into an inactive drug

Question 31

Which types of reactions do CYPs undertake? (phase 1 metabolism)

Answer 31

Phase 1 reactions are ‘ catabolic ’
- Oxidation
- Reduction
- Hydrolysis

Question 32

How do CYPs change drugs?

Answer 32

Non-polar -> polar
Lipid soluble -> water soluble

Polar and water soluble makes it easier to excrete

Question 33

Which types of reactions occur in phase 2 metabolism? (not CYPs - transferase enzymes instead)

Answer 33

Phase 2 reactions are ‘ anabolic ’ (hence associated with conjugation)
- glucuronidation
- acetylation
- sulfation

Aim to make the drug even more water soluble and polar

Question 34

Substrate, Inducer or Inhibitor:
Carbamazepine

Answer 34

CYP450 inducer