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what the body does to the drug (disposition)
pharmacokinetics
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what the drug does to the body (response)
pharmacodynamics
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study of the relationship between single gene variants & variability in drug disposition, response, & toxicity
pharmacogenetics
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study of the relationship between variants in a large collection of genes (up to the whole genome) and variability in drug disposition, response, & toxicity
pharmacogenomics
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difference in the DNA sequence compared with a reference sequence
genetic variant (variation)
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genetic variation that is common (occurs in  1% of the population)
polymorphism
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genetic variation that is rare (occurs in <1% of the population)
mutation
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variable number of nucleotides that are repeated
repeat polymorphism
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abnormal number of copies of one or more DNA regions (eg: gene duplication or deletion)
copy number variation (CNV)
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a variant here may alter TF binding & increase or decrease gene transcription
promoter
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a variant here may change a codon sequence resulting in a different amino acid or premature stop codon (may also have no effect)
exon
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a variant here is least likely to have an effect, but it may have functional consequences if they are linked to other variants in the gene
intron
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a variant here may alter the site of splicing and result in a transcript that lacks exons or contains pieces of introns
in an intron-exon splice junction
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a variant here may alter mRNA stability, structure, or degradation
in the 3' UTR
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DNA sequence at a particular location on a chromosome
allele
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2 alleles at 1 location in DNA
genotype
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alters pharmacokinetics leading to variability in efficacy/toxicity
drug metabolizing enzymes
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alters pharmacodynamics leading to variability in efficacy/toxicity
drug targets
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how decreased metabolizing enzyme fcn affectsÂ
1) drug clearance
2) plasma concentrations
- 1) decreased drug clearance
- 2) increased plasma conc
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if a genetic polymorphism results in multiple copies of a metabolizing enzyme gene, how does this affect:
1) efficacy
2) drug clearance
- 1) decrease efficacy (metabolize faster)
- 2) increase clearance (excreted faster)
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metabolizes S-enantiomer of warfarin
CYP2C9
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CYP2C9 *2
decreases CYP2C9 activity to 60-70%
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CYP2C9 *3
decreases CYP2C9 activity to 5%
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in regards to warfarin, CYP2C9 polymorphisms are associated with ...
decreased warfarin clearance
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(4) difficulties in pharmacogenomic analysis (compared to pharmacogenetics)
- 1) polygenic
- 2) polymorphisms result in subtle effects
- 3) lack of distinct phe dist
- 4) difficult to measure phe's
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enzyme inhibited by warfarin
VKOR (vit. K epoxide reductase)
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effect of VKOR inhibition by warfarin
prevention of vit K recycling -> prevents production of fcnal clotting factors
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VKOR1 genotype assoc'd w/ highest decrease in VKOR
A/A
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