Pharmacogenomics

Question 1

CYP2D6

Answer 1

Genetic Variation in Enzymes
*Codeine
- is a substrate of CYP2D6
- responsible for metabolizing codeine to morphine
• Involved in Metabolism of 25% drugs used clinically
• EM = convert for *analgesic effect
• PM/IM = *Insufficient pain relief
• UM = *Increase risk of adverse effects

Question 2

CYP2C19

Answer 2

Genetic Variation in Enzymes
• Preferentially metabolize acid drugs:
o *Proton-Pump Inhibitors
o *Antidepressants
o *Antiepileptic
o *Antiplatelets: Clopidogrel
o Genetic variances affect how drug metabolizes/therapeutic effect
o PM have higher AUC for PPI, higher intragastric pH, and higher cure rate
• If given PPI–> differences in these factors based on which metabolizer group you are

Question 3

Dihydropyrimidine Dehydrogenase

DPD

Answer 3

Genetic Variation in Enzymes
*DPD: rate-limiting step in pyrimidine catabolism
• Major elimination route of fluoropyrimidine chemotherapy agents:
o *5-fluorouracil (5-FU)
o *Capecitabine
• (~80%) subjected to DPD catabolism
• Deficiency of DPD (or *mutant expression)→ dose-dependent toxicities

Question 4

Uridine 5´-Diphosphoglucuronosyl Transferase 1

(UGT)1A1

Answer 4

Genetic Variation in Enzymes
- UGT1A1: responsible for inactivation of active metabolite of *Irinotecan
• If have mutant form of enz–>low expression–>low elimination–>adverse effects like *leukopenia or diarrhea (assoc w/ Irinotecan)

Question 5

Thiopurine S-Methyltransferase (TPMT)

Answer 5

Genetic Variation in Enzymes
• Agents effected by variants (metabolism):
o *Azathioprine
o *6-mercaptopurine
o *6-thioguanine
o If normal metabolizer → less time of drug in plasma, vs. slow metabolizer
o Normal metabolizer won’t have as many adverse effects/toxicities as slow metabolizers

Question 6

Glucose 6-phosphate dehydrogenase

G6PD

Answer 6

Genetic Variation in Enzymes
- metabolizes *Rasburicase
• *Rasburicase indicated for management of *Uric Acid in patients receiving chemotherapy
• *G6PD deficient individuals at an increased risk for *hemolytic anemia (very serious deficiency!) and methemoglobinemia
• Contraindicated in G6PD individuals

Question 7

Organic Anion Transporter (OATP1B1)

Answer 7

Genetic Variation in Transporters
- OATP1B1: responsible for uptake of mainly weak acid drugs
• Examples:
o *Statins, Lovastatin
o Variant associated adverse effect: *myopathy

Question 8

Drug-Induced Hypersensitivity

Answer 8

Genetic Variation in Immune System Function
- *Human Leukocyte Antigen
• Issues with HLA system
Agents (not exhaustive):
• *NSAIDs
• *Antibiotics
• Steroids
• Abacavir
• *Anti-epileptics
• Many drugs can result in individual experiencing HS
• Generally one of signs is see presentation of *Stevens-Johnson syndrome or *Toxic epidermal necrolysis

Question 9

CYP2C9 & VKORC1

Answer 9

Polygenic Effects
- *Warfarin and INR
• *Vitamin K reductase (VKORC1) target of Warfarin
• *CYP2C9 responsible for metabolizing the drug
• Polymorphisms of VKORC1 and CYP2C9 influence Pharmacokinetics and Pharmacodynamics
o *INR important for those being monitored for Warfarin
o If have variation that causes metabolize diff from rest of population, may have to adjust dose properly to *maintain INR btwn 2-3