Exam3Lec5PersonalizedMedicine Flashcards
What are some examples to personalized medicine?
- BRAF and Vemurafenib =PLX 4032 (required reading for THIS exam period) NEED TO HAVE BRAF MUT
- Duchenne muscular dystrophy and antisense oligonucleotide directed against the splicing target.
ONLY PUTS IT IN FRAME - Bcr-abl and Gleevec (Upcoming, Cancer genetics presentation)
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P450 enzyme examples (two examples, including warfarin, blood thinner)
**a) Degrades drugs that are taken, functions in the liver - N-acetyltransferase 2**
a) Comes in polymorphic versions, decrease leads to acetylation of drugs that inactivates it
6. Thiopurine methyl-transferase (and anti-cancer drug, mercaptopurine)
a) Type of pharmagenetics
bolded is whats in this presentation
pharmacogenetics and pharmacogenomics
What are ways in which individuals can vary in their response to the administration of a drug?
1.Absorption ( blood stream)
2. Distribution (right place)
3. Target binding ( did it bind ritght)
4. Target response
5. Metabolizing (break it down)
6. Excretion ( leave the body)
If a pt has an allele that slowly breaks down drug do you need a higher or lower dose of drug?
Lower dose bc it stays in your body longer
If a pt has an allele that quickly breaks down drug do you need a higher or lower dose of drug?
Higher dose because it does not stay in your body long enough
Explain metabolism and excretion of NSAIDs
Use p450 enzymes in liver to inactivate drugs.
Example 2C9 is a SPECIFC type of p450 enzyme that destroys: Warfrin drug
P450 enzymes inactivate and destroy chemicals that enter the body including drugs
NSAID: Non Steroidal anti inflammatory drugs
Explain Polymorphisms in the 2C9 enzyme
polymorphisms leads to diff amino acids in the poly peptide. With diff amino acids, you break down warfrin differently. You break down the drug either faaster or slower
What does warfarin get metablozed by?
2C9
True or False: the drug warfarin, which is a blood-thinner given to stroke patients, is metabolized differently by the different enzyme variants.
True
How does the vmax in this table relate to how one can degrade warfarin?
Higher vmax= degrade warfarin quicker= Higher dose bc metab quick
Lower vmax=degrade warfarin slower= Lower dose because not metab quick
warfarin is affected differently depending on poly peptide.
What polypeptide you have of 2C9 and adjsust the dosage depending on how fast you degrade warfarin
How does the vmax in this table relate to how one can degrade warfarin?
Higher vmax= degrade warfarin quicker= Higher dose bc metab quick
Lower vmax=degrade warfarin slower= Lower dose because not metab quick
warfarin is affected differently depending on poly peptide.
What polypeptide you have of 2C9 and adjsust the dosage depending on how fast you degrade warfarin
If you are a fast metabolizer of warfarin, will you be a fast metabolizer of any drug that gets broken down by 2C9?
yes. The dose that works well, works well over many different drugs.
Vmax plots represent two 2C9 variant enzymes tested for activity for a variety of different drugs (a-g).
We can use modern technology like ____ that will determine what allele you have and adjust the drug based on that.
microarray
What are the different types of alles you can have with CYP2D6 gene?
- Normal
- reduced fxn mutation
- inactivating
mutation - deletion
- simple duplication
- mutiplex duplication (range of copies)
with multple copies allele, your degrade drug faster.
EXPLAIN THIS PHOTO
this photo on exam
1st arrow from (l to r) represents ultra rapid metabolizers
MORE GENES=MORE COPIES= BREAKDOWN DRUG FASTER=NEED HIGHER DOSE
2nd arrow represents extensive metabolizers
3rd arrow represents intermediate metabolizers
4th arrow represents poor metabolizers
LESS GENES-=DELETED/INACTIVE ALLELE=BREAKDWON DRUG SLOWER=LOWER DOSE
rue or false: based on your ethnicity you can inherit diff types of CYP2D6 alleles
True
EXPLAIN n-acetyltransferase-2
POLYMORPHIC acetylation of aromatic hydrocarbons so you inactivate drug but not the same metabolic process as p450 in the liver.
fast acetylators=drugs goes away fast=need higher dose
slow acetylators=drug goes away slow-need lower dose
same concept as before.
isoniazod is an antibiotic used for TB
Explain TPMT=Thiopurine methyl-transferase (polymorphic)
Mercaptopurine: Circulate easy and taken up
By intestine and stomach (hydrophobic)
Enters cell easy, purine salvage enzyme (HPRT1)
Will add sugar and P to get TIMP which is the substrate for TPMT (by adding methyl) meTimp
TPMT looks like a guanine, causing negative feedback
Inhibition of PPAT (entry point for purine synthesis)
This decreases substrates for DNA synthesis.
Tumor cells want to undergoes BUT No substrates for DNA replication
Mercaptopurine=tx for cancer (trying to halt dna replication)
We give someone this drugs, and it can be easily uptaken by cells. HPRT adds phosp and sugar to make it TIMP. TIMP gets methylated by TPMT to become meTIMP. meTIMP inhibits PPAT which is an entry point for purine synth (RLS). No purines (substrate), no dna made, no prolif of cancer cells,
Explain Enzyme activity for Thiopurine methyl-transferase (TPMT) variants.
variants: tpmt does not work=-drug not effective
homozygous wild type: tpmt works=drug more effective
Higher levels of activity can lead to more meTIMP from wild type, which would lead to more effective inhibition of the purine biosynthesis pathway.
What does the red and green represent in this Clustering software analysis of patient samples for expression of many enzymes related to metabolism of an anti-cancer drug?
Red=high expression=variant= not sensitive (resistant)=not effective
green=low expression=wild type=sensitive to drug=effective
Ras pathway
External ligand binds to TK receptor causing it to dimerize and Phosphorylate each other
This causes GTP exchange (GDP–>GTP) which activates RAS
Downstream signals:
MAP3k|B-RAF methylates
MAP2K|MEK
MAPK| ERK
phosphorylate transcription factors=AP-1
causes proliferations
PLX4032= VEMURAFENIB=potent BRAF inhibitor, selective for V600E
RAS IS A LIGAND NOT TRANSACTIVATOR
