Pharmacogenomics

Question 1

Pharmacogenomics

Answer 1

Study of how an individual’s genetic inheritance affects the manner in which they respond to drugs
“Personalized” medicines

Question 2

P450 CYP2D6

Answer 2

Metabolizes 20-25% of all drugs
Highly polymorphic, inactive in 2-10% of the population
Deficiency can have diverse consequences dependent upon drug
Anti-depressants, anti-arrhytmics, beta blockers, neuroleptics

Question 3

P450 CYP2C9

Answer 3

Metabolizes 15% of all drugs
Estimated 40% of population are heterzygotes
Ex. Warfarin: excessive bleeding: hemorrhage -> fatal

Question 4

P450 CYP2C19

Answer 4

Metabolizes 5% of all drugs
Common in AA and asian populations
Patients with two mutant allels are unresponsive to clopidogrel (the enzymes are defective and cannot convert the prodrug to its active metabolite)

Question 5

P450 CYP3A4

Answer 5

Metabolizes 50% of all drugs
NO INACTIVATING POLYMORPHIC VARIANTS
But grapefruit juice can inhibit this, which affects many drugs

Question 6

N-acetyltransferase (NAT2)

Answer 6

Phase II enzyme; found in liver
Inactivating polymorphisms: lead to inefficient conjugate and SLOW ACETYLATION
This causes increased concentration of drug (because metabolism is slowed down) and side effects:
Isoniazid (antibiotic for tuberculosis): peripheral neuropathy
Hydralazine (antihypertensive): lupus
Sulfonamides (antimicrobial): hypersensitive reactions

Question 7

Pharmacodynamic variability

Answer 7

Drug variability due to polymorphisms/mutations at the site of action
Ex. Warfarin -> VKORC1 is involved in the clotting process, is a target of warfarin. If its a polymorphism warfarin cannot target it