Variability due to genetic difference

Question 1

CYP3A5 (clinically relevant, clearance by this, ethnicity)

Answer 1

Marker: tacrolimus (for immunosuppression)

Clearance: *1/1 genotype have 2x clearance so lower conc versus 3/3 who dont express it

Ethnicity: 80% of caucasians are non expressors, 25% of africans are

Question 2

N-acetyl transferase (clinicals and ethnicity) for acetylation

Answer 2

Marker: procainamide

CR: anti-arrythmics such as ^ and ioniazid (anti tuberculous)

Ethnicity: 50% of caucasians have low clearance, 30% africans 10% (NAT genotype)

Question 3

UGTA1 for glucuronidation (CR, active metabolite, ethnicity)

Answer 3

marker: bilirubin? (people with gilberts lack this enzyme)

CR: anti-cancer drug, irinotecan (pro drug) that is converted to SN-38

Active metabolite: SN-38 is higher in people with low clearance, causing side effects such as neutropenia and diarrhoea

E: common to have poor protein in african americans

Question 4

TPMT with purine metabolism (CR, toxicity)

Answer 4

Marker: 6-mercaptopurine (6-MP)

CR: for acute lymphatic leukaemia and azathiprine which is a pro drug used for people with Crohns and RA

Toxicity: if you have homozygote genotype, need 10 fold reduction in dose

Question 5

Alcohol/ Acetaldehyde dehydrogenase

Answer 5

variations:
-variant of ADH2 leads to increased acetaldehyde= flush
-variant of ALDH2 either increasing acetaldehyde (reduced function) or decreasing acetaldehyde (increased function)
-

Question 6

PGP transporter change causes what?

Answer 6

Multi drug resistance by increasing PGP activity, which lowers drug absorption and transport out (of gut and brain) increased.

(cancer, RA, IBD, epilepsy)

Question 7

Pharmacodynamic example of warfarin, VKORC1 and CYP4F2

Answer 7

Vitamin K must be converted from its inactive form to active form to be recycled (used in CC)

warfarin blocks VKORC1, meaning less inactive form is being turned into its intermediate form (less recycling)

If CYP4F2 which breaks down vitamin K is upregulated, have less vitamin K (lower dose warfarin) and if down regulated more vitamin K in body (need higher warfarin dose). Alter dynamics of warfarin, as warfarin acts on the conversion of inactive to intermediate form.

Pharmacokinetically: CYP2C9 (talked about prior)

Question 8

Explain how the VKOR mutation is thus important

Answer 8

If someone has a VKOR mutation which down regulates it, there is less intermediate vitamin K. If warfarin is given, this will further block the cycle and this is bad, so a lower dose is prescribed