#7 Pharmacogenomics

Question 1

polymorphisms vs. mutation

Answer 1

both are an alteration in the DNA sequence but a polymorphism is present commonly in the population (>1%) while a mutation is rare

Question 2

mutations that impair P450 activity

Answer 2

lead to decreased drug metabolism and increased drug bioavailability. Causes an increase in side effects and toxicity

Question 3

mutations that enhance P450 activity

Answer 3

increases drug metabolism and reduces drug efficacy

Question 4

why is there variability in responses to drugs

Answer 4

polymorphisms in metabolizing enzymes (phase I or II), polymophisms in the site of action for a drug (receptor, enzyme, channel)

Question 5

CYP2D6

Answer 5

phase I enzyme- metabolizes 25% of all drugs

involved in anti-depressent, anti-arrhythmics, beta blockers, and neuroleptic drug metabolism

inactive in 2-10% of the population- enhanced toxicity to drugs metabolized by this enzyme

Question 6

CYP2C9

Answer 6

phase I (15% of all drugs)

40% of caucasians carry defective alleles

metabolizes warfarin and NSAIDS

Question 7

CYP2C19

Answer 7

mutations are more common in asian and black populatoin

Plavix is a prodrug that must be coverted to an active metabolite- if the pt has 2 mutated CYP2C19 genes than they are unresponsive to Plavix

Question 8

N-Acetyltransferase 2 (NAT2)

Answer 8

Phase II enzyme
commonly mutated in the Caucasian population
slow acetylator phenotype

Question 9

phase I clinical trials

Answer 9

small number of healthy human subjects are given the drug. Look for negative side effects (safety profile and pharmacokinetics)

Question 10

Phase IIA clinical trials

Answer 10

drug is tested for desired effect on a small sample size of patients. safety concerns examined

Question 11

Phase IIB clinical trails

Answer 11

further efficacy and does randging are examined with a larger sample size

Question 12

phase III clinical trials

Answer 12

very large sample size (hundreds to thousands of people)

Question 13

Phase IV clinical trials

Answer 13

post marketing follow-up (after the drug is on the market)
adverse events
advantage : larger sample size

Question 14

Her2-Neu

Answer 14

human epidermal growth factor receptor 2
elevated in 25% of breast cancer patients
use FISH analysis to identify gene amplification
pt with elevated Her2-Neu are treated with Herceptin which is a monoclonal antibody against Her2

Question 15

Bcr-Abl

Answer 15

translocation between chromosome 9 and 22 (Philadelphia chromosome - short 22)

cause of chronic myelogenous leukemia (CML)

fusion of two genes brc1 and abl which forms a Bcr-Abl fusion protein with constitutive kinase activity that activated growth and differentiation signal cascades

Gleevec (drug) inhibits Brc-Abl reducing proliferation and activates apoptosis in CML