1-46 Pharmacogenetics

Question 1

Pharmacogenetics

Pharmacogenomics

(a few syndromes)

Answer 1

• Genetics: Effect of a drug influenced mainly by one locus or gene. Trait(s) may exhibit Mendelian inheritance in families.
• Genomics: Effect of drug influenced by multiple loci or genes in combination with non-genetic factors (environment). Inheritance patterns are typically unknown
• glucose-6-phosphate dehydrogenase deficiency (G6PD, Xq28)
• X-linked recessive trait
• malignant hyperthermia susceptibility (RYR1, 19q13)
• autosomal dominant trait
• pseudocholinesterase deficiency (CHE1, 3q25)
• autosomal recessive trait
• clopidogrel poor metabolizer pro drug
• codeince poor metabolizer pro drug
• tacrolimus

Question 2

Types of Inter-individual Variability in Drug Responses

Answer 2

• pharmacokinectice: genes affecting the plasma or tissue drug concentrations
  
  • mostly dues to variations in drug metabolizing enzymes for biotransfromation or elimination of drugs
• pharmacodynamics: direct effect on the inteneded molecular target

Question 3

Nomeclature of cytochrom p450 superfamily

Answer 3

• *1 is always the “normal” reference allel = extensive metabolism
• *1xN = ultra-rapid phenotype, n=number of duplications of the gene
• CYP2D6*1/*3
• CYP: Gene superfamily
  
  • 2: Family
    
    • D: Subfamily
      
      • 6: Isoform
        
        • *1 normal Allele from one parent, *3 abnormal allele from other parent

Question 4

Drug metabolism phenotypes with performance relevance for standard vs prodrugs

Answer 4

Question 5

Effect of CYP2D6 on prodrug metabolism

Answer 5

• codeine is a prodrug to morphine
  
  • •7% of caucasians are poor metabolizers and fail to biotransform codeine to morphine, and have reduced analgesia
  • •Ultrarapid metabolizers can have adverse effects (e.g., respiratory depression) due to rapid formation of morphine

Question 6

Pharmacogenomics of warfarin

Answer 6

• Narrow therapeutic window for anticoagulation
• warfarin inhibits vitamin K oxioreducatse (VKORC1) involved in biosyn of clotting factors by the liver
• given in racemic S and R mixture orally
  
  • S-warfarin eliminated by CYP2C9 in liver
  • Pharmacokinectic: CYP2C9 variants, reduced fxn slow elimination and potentiate anticoagulation
  • Pharmacodynamic: VKORC1 variants influcence efficiacy of dose

Question 7

Pharmacogenomics of codeine bioactivation

Answer 7

• oral analgesic
• pro-drug that requires bioactivation to morphine by CYP2D6
  
  • ​extensive metabolizers = therapeutic effect
  • poor metabolizer = under analgesed
    
    • ​7% white americans
  • ultra-rapid metabolizer = excessive risky sedation

Question 8

Pharmacogenomics of clopidogrel bioactivation

Answer 8

• anti-platelet, for after coronary stenting
• clopidogrel via CYP2C19 -[phase I, bioactivation]> 2-oxo-clopidogrel -> R-130964 (active compound)
• poor metabolizers *2 *3: under-anticoagulated, need higher dose or could clot/MI

Question 9

Pharmacogenomics of proton-pump inhibitors elimination

Answer 9

• Gastric proton-pump inhibitors (omeprazole) treat GERD/ulcers
• Phase I: CYP2C19 and CYP3A4
  
  • CYP2C19 variants:
    
    • poor metabolizers: higher plasma concentration and beter outcomes
    • ultra-rapid metabolizers: clear drug quickly, poor results

Question 10

Pharmacogenomics of thiopurine methyltransferases

Answer 10

• Thiopurines: cytotoxic drugs used to treat leukemia, IBD, organ translplant
• These drugs require conversion to thioguanine nucleotides to expert their anti-cancer/growth effects BUT methylation of the intermediate 6-mercapto purine can stall the conversion (helps slow the drug effects to prevent overactivity)
• Thiopurine Methyltransferase (TPMT) methylates and inactivates 6-mercaptopurine
  
  • Intermediate to low activity of TPMT can cause myelosuppresion or sepsis, dose reduction required, genetic testing performed for kids with leukemia

Question 11

Pharmacogenomics in cancer

Answer 11

• Ex. positive EGFR mutations make some lung cancers more senstive to inhibitors, some mutants also confer resistance