Individual Differences in Drug Metabolism & Pharmacogenomics

Question 1

Phase I: CYP2D6- Genetic Polymorphism

Answer 1

contains allelic variatnts w/ multiple gene copies in tandem

Question 2

Give two examples of the effects CYP2D6 Ultrarapid Metabolizers (URM).

Answer 2

1. Notriptyline—–>inactive metaboilsim
   * unresponsive to normal doses, requires higher dose. will have lower plasma concentration over time
2. Codeine—->Morphine (High levels in plasma)
   * *kids have died from normal doses of codeine after tonsillectomy.

Question 3

What type of population are the rate of URM higher?

Answer 3

30% of middle eastern

Question 4

Phase II contains some slow acetylators. what does the graphical distribution look like?

Answer 4

Bimodal (50% normal & 50% slow)

Question 5

what is the genetic variability of slow acetylators due to?

Answer 5

hepatic acetyltransferase activity (N-acetylation)

Question 6

What population is slow acetylation most common in?

Answer 6

50% of white and african american persons

Question 7

what does slow acetylation lead to ?

Answer 7

prolonged or toxic response to normal doses

Question 8

Give a clinical example of slow acetylation.

Answer 8

-Drug induced lupus erythematosus

Question 9

what are the symptoms in Drug induced lupus erythematosus?

Answer 9

• Fever, arthritis, with + anti nuclear antibodies
• female to male ration 1:1
• no anti dsDNA

Question 10

what are 3 impt drugs which may be problematic in slow acetylation?

Answer 10

1. procainamide (anti-arrythmic)
2. isoniazid (drug of choice for latent TB)
3. Hydralazine (BP medication)

Question 11

What happens in pseudo cholinesterase dificiency? what phase of metabolism is this involved with?

Answer 11

phase I hydrolysis rxn.
-succinylcholine (paralytic)—–>defect pseudo-cholin—–>inacitve metabolism

• neurotransmitter blocker given with anesthetics.
• normal people- dose last 5 min
• psedu-cholin deficient people: last hours.