Pharmacogenomics Flashcards
Describe how genetic polymorphisms in drug metabolizing enzymes can affect standard drug metabolism, serum concentration, efficacy, and toxicity. How do you adjust clinically?
POOR METABOLIZERS (VAR/VAR)
- decreased metabolism
- increased serum concentration of active drug
- increased efficacy
- increased potential for toxicity
- clinical: lower dose, alternative
ULTRA RAPID METABOLIZERS (WT/MC)
- increased metabolism
- decreased serum concentration of active drug
- decreased efficacy
- decreased potential for toxicity
- clinical: higher dose, alternative
Describe how polymorphisms in drug transporter proteins can contribute to drug response variabilities.
DECREASED INFLUX ACTIVITY
- reduced uptake
- decreased efficacy
- if liver: elimination decreased
- potential for toxicity in “off target” tissues
DECREASED EFFLUX ACTIVITY
- reduced excretion
- increased efficacy
- increased toxicity
- decreased elimination
- compromised BBB
Describe how polymorphisms in drug target proteins contribute to drug response variability.
Ex1: reduced copies of promoters => do not respond to drug
Ex2: SNPs in B1 receptors cause downregulation or reduction in GPCRs => do not respond as well
Ex3: polymorphism in downstream signaling molecule => enhanced response to SSRIs => better outcomes
Describe how polymorphisms in VKORC1 contribute to variability in the response to warfarin.
VKORC1 is direct target of warfarin
- -1639G promoter region => higher VKOR => higher dose
- -1639A promoter region => lower VKOR => lower dose (90% of asians)
- rare mutation => reduced affinity of warfarin for VKOR => high dose
Discuss the different mechanisms by which genetic polymorphisms can contribute towards drug-induced adverse effects.
PK-BASED
- polymorphisms in metabolizing enzymes or drug transporters leading to increased serum levels and toxicity (ex: 2C93 and warfarin => bleeding, OATP1B15 and statins => myopathy)
PD-BASED
- polymorphisms in drug targets (VKORC1 and warfarin)
IDIOSYNCRATIC DRUG-INDUCED HEPATOTOXICITY
- most common reason for failed clinical trials and drug recalls
IDIOSYNCRATIC DRUG-INDUCED HYPERSENSITIVITY
- often life-threatening allergic reactions
- FDA recommends genetic screening for asians to prevent steven johnson syndrom
List some of the current barriers to full implementation of pharmacogenetics into clinical practice.
- physician education
- not enough data
- alternative medications
- cost effectiveness
- timeliness
- insurance
- lack of clear clinical guidelines
Define targeted therapy and explain how pharmacogenetic data is used in therapeutic decision making.
- typically used in cancers by identifying specific biomarkers
- ex: herceptin for tumors overexpressing Her2
Contrast polymorphisms in CYP3A4 vs CYP2D6, 2C19, and 2C9.
CYP2D6, 2C9, 2C19
- very polymorphic
- significant variations
- clinically significant
CYP3A4
- rare polymorphic alleles
- little variation
- redundancy with CYP3A5
- not significant
Describe the clinical relevance of CYP2C9 polymorphisms with regards to warfarin.
Warfarin is given as a prodrug. CYP2C9 is responsible for inactivating the active S-warfarin. Those with 2C92/3 polymorphisms have decreased metabolism =>
- increased concentration of active warfarin
- bleeding events
- requires lower dosing
Those with CYP2C915/25 polymorphisms are null.
Describe the clinical relevance of CYP2C9 polymorphisms with regards to warfarin.
Warfarin is given as a prodrug. CYP2C9 is responsible for inactivating the active S-warfarin. Those with 2C92/3 polymorphisms have decreased metabolism =>
- increased concentration of active warfarin
- bleeding events
- requires lower dosing
Those with CYP2C915/25 polymorphisms are null.
Describe effects of polymorphisms in Phase II enzymes.
- decreased elimination
- increased risk for toxicity
Describe genetic polymorphisms of OATP1B1 drug transporter.
OATP1B15/15
- decreased hepatic uptake of statins
- reduced efficacy
- increased serum concentration
- increased toxicity/accumulation in muscles
- clinical: reduced dose
