Phase I drug

Question 1

CYPs in humans which are important in metabolising drugs

Answer 1

• 3A4 –> liver

- 2D6 –> not well expressed

Question 2

Important properties of CYPs that can influence therapy

Answer 2

• inhibited drug: drugs compete with each other for enzymes is high and gives rise to pharmacokinetics drug-drug interaction
• some are inducible- where exposure of the drug can increase the expression or amount of CYP in the liver

Question 3

Pharmacogenetic variation

Answer 3

some individuals who carry defect copies of CYD2D6 unable to metabolise the drug which rely on enzyme to eliminate , thus there is build up of the drug - inhibitory drug interaction

Question 4

CYP3A4

Answer 4

• major in human liver
• many drugs metabolised by this enzyme
• readily inhibited (inhibitory drug interaction) i.e. grapejuice
• Highly inducible e.g. St John’s wort or rifampicin

Question 5

CYP3A4 : Some important drugs classes include

Answer 5

 Statins (high cholesterol)
 HIV protease inhibitors – drug used to elongate the drugs for HIV by inhibiting the degradation of the drugs used for HIV
 Benzodiazepines (high blood pressure)
 Calcium channel blockers

Question 6

CYP3A4 inhibition: between triazolam and diltiazem

Answer 6

triazolam is a CYP3A4 substrate.
When T and D are together, D prolongs the half-life and increased Cmax. Thus the levels of Triazolam have increase as not being eliminated. When diltiazem levels decrease, the blood levels will come down and allow Triazolem to decrease as well

Question 7

Grapejuice vs Felodipine

Answer 7

It was found that grapejuice increased absorbed drug and bioavalibility. increased felodipine Cmax

Grapejuice inhibits CYP3A4 intestinal. Thus undergoes presystemic oxidation in the intestines.

GJ increases the amount of felodipine absorbed

Question 8

CYP3A4 induction

- clinical significance

Answer 8

• increased clearance of the drug metabolised by CYP3A4
• diminishes therapeutic effect
• reduces systemic exposure
• this reduces the amount of drug absorbed into the body as shortening half-life of drug

Question 9

Example of CYP3A4 induction

Answer 9

Pregnane X-receptor:

• forms a dimer with RXR
• dimer translocate to the nucleus where it is able to activate the expression of genes and switch on enzymes like CYP3A4

Question 10

CYP1A2

- metabolism

Answer 10

• gene is inducible by cigrette smoke
• aryl hydrocarbon receptor (AhR)
• PAH moves into the cell to interact with AhR in the nucleus, which stimulates the expression

Question 11

CYP1A2

- clinical significance

Answer 11

• smokers who receive toxic drugs (antipsychotic drug) i.e. clozapine rapidly eliminate that drug
• can be toxic if the smoker stops smoking, and continues with that dosage, the CYP1A2 will decrease, thus less of the drug is being cleared and more building up

Question 12

CYP2D6

- debrisoquine hydroxylase

Answer 12

• antihypertensive drug

- varied dosage for each individual as the rate of drug being metabolised varies for each patient

Question 13

CYP2D6

- codeine and tamoxifen

Answer 13

Pro-drugs, low activity but once when in body with the activation of CYP2D6. People who lack this enzyme, are not able to get the pain relief or treatment for breast cancer

Question 14

CYP2D6 - extensive metabolisers

Answer 14

carry two active alleles - normal people

Question 15

poor metabolisers

Answer 15

carry two non-functional alleles - exhibit slow clearance of CYP2D6 subtrates and poor activation of pro-drugs i.e. codeine

Question 16

intermediate metabolisers

Answer 16

carry two low activity alleles (one active, one not)

Question 17

ultrarapid metaboliser -

Answer 17

carry multiple copies of the CYP2D6 gene

Question 18

what happens if they have too many copies of the gene

Answer 18

they form a lot of metabolites, as they rapidly convert metabolite as won’t be cured from depression as drug won’t be able to be absorbed and those who lack the copies of genes will have toxic levels