Pharmacogenetics

Question 1

Phase I Enzymes

Answer 1

• CYP2D6
• CYP2C19
• CYP3A4 and CYP3A5
• Dihydropyrimidine Dehydrogenase (DPD)
• CYP2C9

Question 2

CYP2D6

Answer 2

• Metabolizes 20-25% of drugs
• Many polymorphisms characterized, but only ~ 9 are common
• Most pts are “extensive metabolizers”
• A small percentage are “poor metabolizers”
• More likely to have adverse rxn to psychoactive meds metabolized by this pathway
• ↓ Ability to metabolize codeine → morphine ⇒ ↓response
• “Ultra-rapid metabolizers” ⇒ ↑response to codeine

Question 3

CYP2C19

Answer 3

• Metabolizes relatively few drugs
• Responsible for metabolism of clopidogrel (anti-platelet) and omeprazole (PPI) among other drugs
• Clopidogrel is metabolized to the active drug
• Poor metabolizers ⇒ ↓ concentrations of active metabolite ⇒ ↑ likelihood of developing clots
• Rapid metabolizers ⇒ ↑ risk of bleeding
• Poor metabolizers ⇒ ↑ concentration of omeprazole and rapid metabolizers ⇒ ↓ concentrations

Question 4

CYP3A4 and CYP3A5

Answer 4

• Metabolizes over 50% of drugs
• Relatively few polymorphisms alter pharmacokinetics to a significant degree

Question 5

Dihydropyrimidine Dehydrogenase (DPD)

Answer 5

Major metabolic pathway for clearance of 5-fluorouracil (5-FU)

↓ DPD activity ⇒ ↑ 5-FU ↑ toxicity ⇒ dosage will need to be reduced

Question 6

CYP2C9 and VKORC1

Answer 6

• Together account for ~ 40% of genetic variability in metabolism of warfarin
• Underactive versions of CYP2C9 ⇒ toxicity unless dosage is reduced
• VKORC1 (vitamin K epoxide reductase) ⇒ activation of vitamin K
• Pts w/ less active VKORC1 ⇒ relatively less vitamin K ⇒ slow down clotting process ⇒ ↓ dose of warfarin necessary to achieve the same effect

Question 7

Phase II Enzymes

Answer 7

• Polymorphisms in thiopurine methyltransferase ⇒ ↓ inactivation of 6-mercaptopurine and azathioprine
• Will enhance toxicity of these agents, esp. if one of the other metabolic pathways ⊗ by allopurinol

Question 8

Transporters

Answer 8

• 2% of pts more likely to experience weakness and muscle pain at higher doses of statins
• Single polymorphism in SLCO1B1 ⇒ significant portion of these adverse effects
• Homozygous for the variant ⇒ 16x higher risk of rhabdomyolysis
• Gene codes for an organic anion transporter ⇒ facilitates uptake of drugs like statins and methotrexate into hepatocytes
• ↓ transporter function ⇒ ↑ concentration of drug and potential for toxicity

Question 9

Other Significant Polymorphisms

Answer 9

Polymorphisms in certain HLAs ⇒ ↑ immunologic response to certain drugs such as abacavir

G6PD deficiency ⇒ ↓ glutathione in RBCs ⇒ ↑ susceptible to oxidative stress caused by certain drugs such as primaquine

Major metabolic pathway for succinylcholine via action of pseudocholinesterase

Inactive variant ⇒ prolonged response

Question 10

Cancer

Genetic Testing

Answer 10

Only HER2 ⊕ breast tumors will respond to mAb trastuzumab

Activating mutations in EGFR in pts w/ non-small cell lung cancers can predict response to gefitinib (EGFR inhibitor)

Tamoxifen (estrogen receptor antagonist) requires activation to active form via CYP2D6

Slow metabolizers less likely to respond to this agent