Pharmacogenetics Flashcards
Pharmacogenetics
Differences in drug response due to allelic variation in genes affecting drug metabolism, efficacy, and toxicity.
Involves study of a few genes (they are selected based on previous knowledge of their roles in drug metabolism)
Genocopy
Mutation in different gene causing the same syndrome
Phenocopy
Syndrome caused by environmental factor
Pharmacogenomics
Assess common genetic variants in the aggregate for their impact on the outcome of drug therapy.
Instead of analyzing individual genes and their variants, sets of alleles at a large # of polymorphic loci are being identified that distinguish patients who have responded adversely
Pharmacokinetics
Rate at which body absorbs, transports, metabolizes, or excretes drugs or their metabolites. (ex: cytochrome P450, glucuronyltransferase).
Whether or how much drug reaches the target?
Pharmacodynamics
The response of the drug binding to its targets and downstream targets, such as receptors, enzymes, or metabolic pathways.
ex: G-6-P dehydrogenase, vitamin K.
What happens when the drug successfully reaches its target?
Pharmacokinetics phases
Phase I: attach polar group to make it more soluble, often hydroxylation
Phase II: attach a sugar/acetyl group to detoxify the drug and make it easier to excrete.
Where are cytochrome P450 (CYP450) found?
In liver and epithelia of small intestine
When are CYP1, 2, and 3 families most active?
In Phase I metabolism of 90% of commonly used meds
CYP is usually…. but sometimes….?
CYP genes are usually important in rate of inactivation, but they can also be required to ACTIVATE a drug (ex: codeine, inactive to morphine, active and potent)
Types of mutations in CYP genes?
- Frameshift, alter reading frame, NO activity
- Splicing, skip exons/alter reading frame, NO activity
- Missense, alter protein fx, REDUCED activity
- Copy number alleles, increased gene copy alleles, increased (ULTRAFAST)… need lower dose.
Based on these combos you can be:: normal, poor and ultrarapid/ultrafast.
Grapefruit juice
Can inhibit CYP3A. Which means it inhibits phase I (so drug is not made soluble), so the drug is bad and can lead to bad side effects. (drug is made more bioavailable).
INCREASE BIOAVAILABILITY
Cyclosporine
When you add anti-fungal ketoconazole this inhibits CYP3A metabolism, so you get increased levels of cyclosporine (can be toxic).
CYP3A
Cyclosporine.
Genetically less important b/c population distribution is continuous and unimodal.
Inhibitors: ketoconazole, grapefruit juice
Inducers: rifampin
CYP2D6
Tricyclic antidepressants. Codeine.
Multiple (frameshift, splicing, missense, gene duplications)
Inhibitors: quinidine, fluoxetine, paroxetine
