5. Pharmacogenetics And Pharmacogenomics Flashcards
- To understand the uses of pharmacogenomic information in drug choice, monitoring and dosing (objective)
Answer later
- To understand how genetic polymorphisms can affect the pharmacokinetic and pharmacodynamic properties of a drug (objective)
Answer later
- To understand specific examples of pharmacogenetic differences and how they impact therapeutic and adverse drug responses (objective, see list below)
Answer later:
- Common cytochrome P450 polymorphisms and their effects on drug metabolism
- Isoniazid fast and slow acetylators
- Thiopurine methyltransferase and the use of purine analogs as anti-cancer agents
- Roles for glucose-6-phosphate dehydrogenase variants in drug-induced hemolysis
Pharmacogenetics (definition)
Influence of genetic variability on drug responses (both therapeutic and toxic drug responses)
Pharmacogenomics (definition)
Use of genetic information to predict drug responses
Genetic differences may influence:
Pharmacokinetics of a drug: effects on ADME
Pharmacodynamics of a drug: effects on mediators of a drug’s action: both the direct target (receptor) with which the drug interacts and other processes (signal transduction pathways) that mediate a drug’s action
Percentage of drugs influenced by actionable pharmacogenes
7% of FDA-approved medications are affected by actionable inherited pharmacogenes
18% of US outpatient prescriptions are affected by actionable germline pharmacogenomics
Pharmacokinetic examples: Phase 1 Enzymes
CYP2D6
Cytochrome P450 2D6 responsible for metabolism of 20-25% of all medications
Metabolizes several classes of drugs:
Antidepressants, antiarrhythmics, B-adrenergic receptor antagonists and analgesics
CYP2D6 Polymorphisms
Four phenotypes:
- Poor metabolizers (PM)
- Intermediate metabolizers (IM)
- Extensive metabolizers (EM)
- Ultrarapid metabolizers (UM)
Effect of CYP2D6 genetic polymorphisms on survival of women with ER(+) breast cancer treated with tamoxifen
Tamoxifen used in treatment of estrogen receptor ER(+) tumors
Tamoxifen is a prodrug
CYP2D6: nortripyline metabolism
Later
CYP2D6: codeine
Later
Additional consideration: drug interactions
Multiple drugs are CYP2D6 inhibitors
Classified as strong (fluoxetine, paroxetine), moderate (sertraline, duloxetine), and weak (buprenorphine)
Pharmacokinetic examples: Phase II reactions
Isoniazid metabolism by NAT2 enzyme
Thiopurines metabolism
Isoniazid Metabolism
Used for treatment of tuberculosis
Metabolized by N-acetyltransferase 2 (NAT2), a phase II enzyme
Slow acetylators and Fast acetylators
Later
Clinical Significance of Isoniazid Acetylation Rate
Influence of acetylation rate on the anti-tuberculosis activity is uncertain.
It does appear that the rate of acetylation influences isoniazid toxicity: slow acetylators are more prone to suffer from isoniazid toxicity, including peripheral neuropathy
Metabolism of Thiopurines
- Used to treat autoimmune conditions (Crohn’s disease) and acute lymphoblastic leukemia and prevent organ transplant rejection
- Thiopurines include 6-mercaptopurine (6-MP) and azathioprine (AZA), have relatively low therapeutic index
- Neither 6-MP nor AZA has intrinsic activity, undergo biotransformations leading to formation of 6-thioguanine nucleotides (6-TGNs) that have cytotoxic effects and are incorporated into DNA
- Thiopurines inactivated by thiopurine S-methyltransferase (TPMT)
Frequency distribution of red blood cell (RBC) thiopurine S-methyltransferase (TPMT) activity
20 variant alleles of TPMT
TPMT*2/3A/3C are defective alleles that encode for proteins with reduced catalytic activity
Dosage Adjustment
Administration of standard doses of thiopurines to individuals with reduced or undetectable TPMT activity may produce life-threatening adverse events (myelosuppression, bleeding, severe infection). Need to reduce drug or use alternate drug.
Patients with high TPMT activity may display reduced response to standard doses of thiopurines and may require increased doses to get therapeutic response.
Pharmacokinetic Examples: Other (not Phase I or II) Enzymes
Glucose 6-phosphate dehydrogenase
Glucose 6-phosphate dehydrogenase
G6PD is rate-limiting step of PPP and role in maintaining NADPH and GSH levels
In RBC’s, G6PD is exclusive source of NADPH and GSH
If G6PD deficiency, at increased risk for hemolysis when exposed to oxidative stress (infection, fava beans, certain drugs) due to reduced antioxidant capacity
G6PD
Deficiency, can develop haemolytic anaemia after eating broad beans or taking drug rasburicase.
G6PD Deficiency
Defined as less than 60% activity
G6PD Variants
Gene on X chromosome
180 genetic variants (90% single-base substitutions) for reduced catalytic activity
Hemizygous-deficient males and homozygous-deficient females express reduced activity phenotypes
Due to X-chromosome mosaicism, G6PD activity in cells from heterozygous females may range from fully functional to severly deficient
Pharmacodynamic Examples
B2-adrenergic receptor polymorphisms
Gefitinib and EGFR mutations
B2-adrenergic receptor polymorphisms influence bronchodilator response in asthma
B2AR agonists (albuterol) treat asthma
Two polymorphic loci in the coding region of receptor: Gly-16/Arg-16 and Glu-27/Gln-27
Children study:
Mutation in first loci children more likely to respond to albuterol
No association in second loci in response to albuterol
Gefitinib and EGFR Mutations
Gefitinib is a tyrosine kinase (TK) inhibitor that targets the epidermal growth factor (EGF) receptor (used to treat non-small-cell lung cancer)
Most patients don’t respond to gefitinib, but 10% display rapid therapeutic response
High sensitivity due to somatic mutations clustered around ATP-binding pocket of EGFR TK domain.
Mutations associated with increased EGF-stimulated TK catalytic activity and increased sensitivity to gefitinib inhibition.
Challenges in implementing pharmacogenomics
Need for means to compare adverse reactions associated with a drug across multiple studies
Imaging and biomarkers may help
