Lecture 4: Principles of drug individualization Flashcards
DNA –> ____ –> mRNA
transcription
mRNA –> ____ –> tRNA –> ____
translation; polypeptide
gene
segment of DNA that contains info for encoding a protein
SNPs
single nucleotide polymorphism
alleles
different DNA sequences at a locus
genotype
pair of alleles at a particular locus (ex: GA)
phenotypes
observable property of an organism; a trait such as height, weight, medical condition etc
haplotype
a set of DNA variations, or polymorphisms, that tend to be inherited together (within a chromosome)
What is an important factor in the history of pharmacogenomics?
diversity – factors that make individual or subgroups different
can the same drug have different responses?
yes
genotypes determine what?
phenotype
What factors affect the drug response
1.) environment
- diet
- lifestyle
- socioeconomic
- others
2.) biology
- age
- sex
- others
3.) genetics
Why personalized/individualized medicine?
Dosage - means and medians derived from clinical trials
- relatively homogenous populations
- caucasian, adult (middle-aged), no co-morbidities, middle-of-the-curve
outcomes - derived from clinical trial
- altered if post-marketing surveillance data indicate a need
results - many pts receive inappropriate drugs or dosages because they are not “middle of the curve”
What is pharmacogenomics?
the study of how genes affect a person’s response to drugs
What are the goals of pharmacogenomics
getting the right dose of the right drug to the right pt at the right time
- to enhance drug efficacy and reduce drug toxicity
pathway of drug after administration
dose of drug administered
ABSORPTION
drug [ ] in systemic circulation
DISTRIBUTION
drug [ ] at site of action
pharmacological effect
clinical response –> toxicity or efficacy
systemic approach to genetic variations
identify the genetic variations and what can be affected
- enzyme, transporter, receptor, disease
- silent: no fxnal effect
determine who is impacted
- individuals or population
identify how it is relevant to drug
- affect drug PK or PD
- resulted in drug efficacy, toxicity, or drug dosing
- has no effect
determine how relevant to a disease
- increase or decrease drugs susceptibility or condition
- utility as a screening or diagnostic tool
how can a drug dose PO be different when absorbed by the body compared to IV/IM dose
The first-pass effect decreases the active drug’s concentration upon reaching systemic circulation or its site of action. (needs higher dose)
PGX and metabolism classifications
phase I rxn:
Oxidation
Hydroxylation
Reduction
Hydrolysis
phase II rxn
Conjugation
genetic variations and enzymatic activity (phenotypes)
- extensive metabolizes (EM or WT)
- poor metabolizer (PM)
- intermediate metabolizer (IM)
- ultra-rapid metabolizer (UM)
What are extensive metabolizers (EM or WT)
individuals who are homozygous for the 2 alleles coding for normal enzyme fxn
what are poor metabolizer (PM)
individuals who are homozygous with 2 variant alleles resulting in inactive or absent enzymes
what are intermediate metabolizer (IM)
those who are heterozygous manifest phenotype with reduced fxn of heterozygous EM
what are ultra-rapid metabolizers (UM)
resulted from gene duplication or multiplication
PGx of metabolizing enzymes
tamoxifen efficacy
TAM must become activated with a hydroxyl group via CYP2D6 enzyme to become ENDOXIFEN
ER antagonist and breast cancer - what happens with the overall recurrence rate and all-cause mortality if EM and PM given same dose?
the overall recurrence rate and all-cause mortality rates will increase
irinotrecan genetic variant/marker and effect
UGT1A1*28
neutropenia
codeine (prodrug) genetic variant/marker and effect
CYP2D6
PM - no analgesic effect
UM - respiratory depression
Clopidogrel (prodrug)
CYP2C19
PM - no drug activity
