04,05 Drug metabolism and Pharmacogenetics

Question 1

phase I reactions

Answer 1

oxidation, reduction, dealkylation, hydrolysis

Question 2

Phase I required proteins/molecules

Answer 2

• cytochromes p450
• p450 reductase (flavoprotein)
• NADPH
• O2

Question 3

Flavin monooxygenase

Answer 3

(FMO)

• Alternate enzyme for Phase I (instead of cytochrome p450)
• Less variability because fewer polymorphisms

Question 4

List important p450s (6)

Answer 4

3A--grapefruit juice
2D6--antidepressants, whites
2C9--warfarin
2C19--asians, 3 drugs
2E1--acetaminophen
1A2

Question 5

Phase II reactions:

• most common
• their enzymes
• order according to # of drugs handled

Answer 5

(listed in order of # of drugs handled, starting with most)

1. Glucuronidation–UGT (UDP gluronosyl transferase)
2. Acetylation–NAT (N-acetyltransferase)
3. Sulfonation–SULT (sulfotransferase)
4. Glutathione conjugation–GST (glutathione S-transferase)

Question 6

NAT-2

Answer 6

• Metabolizes: Isoniazid (anti-TB)

- Fast allele is dominant, so poor metabolizers are homozygous

Question 7

CYP 2D6

Answer 7

• metabolizes: Antidepressants

- 10% europeans

Question 8

CYP 2C19

Answer 8

Metabolizes:

1. Phenytoin :( (anti-convulsant)
2. Omeprazole :) (proton pump I)

Activates:
3. Clopidogrel :( (anti-platelet)

-55% asians

Question 9

CYP 2C9

Answer 9

• metabolizes: Warfarin
• activates: Codeine to Morphine

-Always think VKORC1 for warfarin

Question 10

VKORC1

Answer 10

• Warfarin binds to this protein complex to block clotting cascade.
• Asians–more sensitive
• Blacks–less sensitive

-Always think CYP 2C9 for warfarin

Question 11

Pseudocholinesterase

Answer 11

• metabolizes Succinylcholine (depolarizing muscle relaxant)

- dangerous for poor metabolizers

Question 12

TPMT

Answer 12

• metabolizes Mercaptopurine

- danger of bone marrow suppression in poor metabolizers

Question 13

Pgp (P-glycoprotein)

Answer 13

• Active transport of Digoxin into GI lumen from mucosa

- Digoxin toxicity if less Pgp