71/72: Pharmacogenomics Flashcards
pharmacogenetics =
study of how the genetic basis for variations in drugs response
study of how variation in single gene influences the response to a single drug
pharmacogenomics =
study of how all the genes can influence responses to drugs
monogenic v. multigenic responses
monogenic = variation in single gene causing dif in specific drug response
multigenic = variation in multiple genes causing dif in specific drug response
mutation =
difference in DNA code that occurs in less than 1% of the population
polymorphism =
difference in DNA code that occurs in more than 1% of the population
allele =
one of a number of alternate forms of a gene
within a population, there can be many alleles of a particular gene, one person can have two alleles.
synonymous v. nonsynonymous SNPS
base pair change does not cause aa substitution (can change prtn expression/ splicing)
base pair change leads to aa substitution
non-coding SNPs can alter
- transcription factor binding
- splicing
- transcript stability
- enhancer function
complete deletion or duplication of a particular gene
copy number variants
gain or loss of function
cosmopolitan v. population polymorphisms
cosmo: common across all ethnic groups
pop: differ between groups
phenotype-to-genotype approach
start out by directly measuring pharmacogenetic trait (enzyme activity, phsyiological response, drug levels in body)
+ sum of all genes giving rise to effect
- non-genetic influences giving rise to and unstable responses
then, genotype individuals from each phenotype group to determine differences in DNA sequence ( candidate gene approach or genome-wide approach)
3 pharmacogenetic phenotypes
PHARMACOKINETIC - effect of polymorphism in a gene that regulates pharmacokinetics (metabolic enzymes or drug transporters)
- alters drug concentrations
PHARMACODYNAMIC - effect of polymorphism in gene that codes fro drug targets such as receptors or enzymes
- alters drug response
INDIRECT - effects of polymorphisms in a gene that does not interact with drug, not involved with disposition of drug
CYP2D6
ultrametabolizers (3/2 genes) –> poor (0/2) metabolizers
- tamoxifen
- codeine
- SSRI paroxetine
tamoxifen
CYP2D6 status
needs to be activated using this gene
tamoxifen metabolites competitive inhibit estrogen receptor (needs to have functional CYP2D6 to work)
codeine
converted into active morphine by CYP2D6
analgesia (need enough -poor) and side effects (too much - ultra) need to be considered with mutations
SSRI paroxetine
paroxetine is degraded by CYP2D6
CYP2C19
- clopidogrel
- omeprazole
- lansoprazole
clopidogrel
activated by CYP2C19 in liver
anticoagulant drug
omeprazoel and lansoprazole
metabolized by CYP2C19
PPIs
Warfarin
CYP2C9 clears and inactivates warfarin
VKORC1 (pharmacodynamic) mutations need to decreases warfarin because the enzyme already works less
5- Flurouracil 5FU
DPD dihydropyrimide dehydrogenase
- inactivates active form of drug
TYMS thymidylate synthetase
- drug target; polymorphisms can increase or decrease activity
- pharmacodynamic
MOA: damages DNA by lowering dTTP levels and by being incorporated into DNA
6-mercaptopurine 6MP
TPMT thiopurine methyltransferse
- inactivates the drug
simvastatin induced myopathy …
associated with specific SNP on gene in chromosome 12 - SLCO1B!
- effects liver uptake of simvastatin - decreased activity - more in plasma - more adverse effects (myopathy)
polymorphisms in estrogen receptor ERa
homozygotes for less common allele had a greater increase in HDL (good cholesterol) levels following HRT
pharmacodynamic
albuterol
polymorphism at 16th aa residue of ADRB2 decreases effectiveness of albuterol
arg/arg phenotype - don’t use
normal gly/gly phenotype - use albuterol
smoking (envirnoment) also effects
polymorphisms in factor V and prothrombin _______ risk of VTE with oral contraceptives
increase
indirect pharmacogenetic phenotype
abacavir
HIV drug
individuals with HLA-B*57:01 allele have a high risk of having hypersensitivity reaction to abacavir
indirect pharmacogenetic phenotype - no effect on pharmacokinetics or pharmacodynamics of abacavir
tacrine
therapy for alzheimers disease
absence of certain alleles in APOE gene correlates with better therapeutic success
indirect pharmacogenetic phenotype
predicted response to interferon alpha tx for hep C
SNP polymorphism in Il-28 gene- no polymorphism = better
indirect pharmacogenetic phenotype
