Pharmacogenetics Flashcards
What response of drug variability is d/t SNPs?
55-70%
What is the polymorphism that is responsible for the “Asian flush?”
ALDH2*2 = inactive form of the allele, present in 40% of Asians
Also much higher risk of esophageal cancer
SNP variation vs mutation
Variation: >1% of population
Mutation: <1% of population
TNFa gene variation
“G” allele turns on inflamm factors
“A” allele causes OCT1 to bind and increase susceptibility to cerebral hemorrhagic during infection d/t double amt of promoters
3 forms of SNP variance that affect phenytoin reponse
CYP2c9/Cyp2c19
MDR1 gene promoter
Voltage gated Na channels
How does CYP2C9/CYP2c19 affect phenytoin levels?
Dec CYP activity Dec metabolism Inc blood levels Ataxia, slurred speech, confusion DECREASE dose
How does MDR1 gene promoter affect phenytoin levels?
Inc gene transcription Inc levels at BBB Inc drug extrusion Low levels in brain INCREASE dose
How do variations in voltage gated Na channels affect phenytoin response?
Poor binding affinity to phenytoin
SWITCH med
Which test is used to guide dosing in warfarin pts and what does it look for?
Nanosphere test
Determines allele make up of CYP2C9 and VKORC1
What is the issue with the nanosphere test?
Doesn’t test in African Americans
What are roles of VKORC1 and CYP2C9 when it comes to warfarin?
Warfarin inhibits VKORC
CYP2C9 inactivates warfarin
Allele variants in warfarin users
Wild type = CYP2C91
Inactive = CYP2C92, CYP2C9*3 (inc bleeding risk)
VKORC1 A allele = low activity, inc ADR
What does 5FU do?
Inhibits TS activity in tumor cells, inactivated and metabolized by DPD
5FU allele variations
DPD*1 = wild type (homozygous G) ADR = heterozygous in active A allele -> inactive DPD -> 5FU not inactivated -> fatal myelosuppression
Triple tandem TS repeat = lower reponse to 5FU
Main p450 families involved in drug metabolism
CYP1-3
