Pharmacogenomics Flashcards
1842 First human drug metabolism experiment by Keller showed ________ acid converted in urine to hippuric acid
benzoic acid
______________ : study of the relationship between variations in a single gene (or small collection of genes) and variability in drug disposition, response, and toxicity.
pharmacogenetics (PGx)
_______________ : study of the relationship between variations in a large collection of genes (up to the whole genome) and variability in drug disposition, response, and toxicity.
pharmacogenomics
The liver’s primary mechanism for metabolizing drugs is via a group of cytochrome____________ enzymes
P-450
___________: mathematics of the time course of Absorption, Distribution, Metabolism, and Excretion of drugs
pharmacokinetics
Drug metabolism is usually monogenic/multigenic?
monogenic
Polymorphisms can affect protein function and can make ____________ bimodal or even trimodal
distribution
Variable ______________ phenotypes may influence drug dosing, efficacy, and/or toxicity
pharmacokinetic
Genetic variants in a metabolizing enzyme can alter enzyme _________, enzyme _________ or inactivate the enzyme
activity, affinity
Genetic variants in a metabolizing enzyme can ___________ clearance, ___________ the AUC and ______________half-life
decrease clearance
increase AUC
increase t1/2
Duplications/multiplications in a metabolizing enzyme are more rare but can ___________ clearance, ___________ the AUC and ______________half-life
increase clearance
decrease AUC
decrease t1/2
The impact of drug metabolizing enzyme gene variants on the pharmacologic effect and toxicity profile of a drug depends, in part, on whether the drug is active in its parent form or is a ___________
prodrug
Star nomenclature is typically numbered in order of _____________
discovery
1 / (1A/B/C) are typically ____________ allele
reference/normal
Some * alleles are defined by the presence of more than 1 variant in _____
Phasing is required
cis
Interpretation of phenotype requires knowledge of ____________, not just genotype
diplotype
Break down CYP-2-C-19-17
CYP2C192
CYP2C19*3
Superfamily - CYP
Family - 2
Subfamily - C
Gene - 19
Allelic variant *17 increased function
*2 and *3 are no function alleles
= Tier I variants
FDA box warning discusses testing of _______________ for Plavix
CYP2C19
___________ collects, curates and disseminates knowledge about the impact of human genetic variation on drug responses.”
PharmGKB
PharmGKB Clinical Annotation Levels of Evidence
1A/B high, 2A/B moderate, 3 low, 4 preliminary
PharmGKB may state that genetic testing for a drug is ____________ or ____________ and that it is _____________ or __________________
required or recommended
actionable or informative
CPIC (2009 PGKC and PGRN) stands for ______________ ________________ _______________ _______________
Clinical Pharmacogenetics Implementation Consortium
CPIC currently has ______________ guidelines
33
_______________ is linked to statin-induced myopathy
SLC01B1
SLCO1B1 : Gene expressed at the hepatic ____________ membrane that reabsorbs a variety of chemicals from plasma into the liver
sinusoidal
*____ allele of SLC01B1 rs4149056 / p.Val174Ala results in lower transport into liver and decreases clearance of simvastatin = lower dose means that patient has greater exposure to active drug
5
SLCO1B15
Number needed to __________________ is the number of tests that must be performed to affect healthcare
genotype (like number needed to treat)
SLC01B1*5 rs4149056 involves a ______ to ________ mutation at 174
Val174Ala
_______ is the enzyme that metabolizes fludarabine and capecitabine and is important in GI oncology treatment toxicity
DPYD (dihydropyrimidine dehydrogenase)
_______ is the enzyme that metabolizes irinotecan and is important in GI oncology treatment toxicity
UGT1A1 uridine diphosphate (UDP) glucuronosyltransferase 1A1
________ and _______ are examples of phase II drug metabolizing enzymes
UGT1A1 and TPMT
_______ and _______ are examples of phase I drug metabolizing enzmes
CYP and DPD
_______ and ______ metabolize coumadin
CYP2C9 and VKORC1
___________ is responsible for metabolizing clopidogrel, voriconazole, PPIs and SSRIs
CYP2C19 (10q23.3)
Is clopidogrel an active drug or prodrug?
prodrug
Phase I drug metabolism is characterized by _______, ________ and ___________ reactions
oxidation, reduction and hydrolysis
Phase II drug metabolism is characterized by ___________ reactions
conjugation
____________ is an inducer that increases CYP2B6, 2C8, 2C9, 2C19, 2D6, 3A4, 3A5
rifampin
Grapefruit juice and St Johns wort inhibit __________ drug metabolism
CYP3A4
___________ is an inducer of CYP1A2
broccoli
Two no function alleles makes for a/an __________ metabolizer
poor
A normal function allele and a no function allele make for a/an _____________ metabolizer
intermediate
Diplotype if no variants are detected (not present or not in the assay design)
1/1
__________ is a phase I enzyme responsible for metabolizing about 21% of approved medications including warfarin and phenytoin
CYP2D6
CYP2D6 has over 130 star ________ as well _________, _________ and ____________ alleles. It is also subject to ________ and _______
alleles, deletions, duplications, hybrid (with pseudogene CYP2D7)
induction and inhibition
In addition to the phenotype, a CYP2D6 diplotype also has an _________ _________
activity score
Ultrarapid >2,25
Normal 1.25-2.25
Intermediate <1.5
Poor metabolizer 0
CPIC currently has guidelines for __________ medications with CYP2D6
14 *FDA has 20
tamoxifen (cancer)
atomoxetine, SSRI, TCAs (mental health)
codeine, tramadol, hydrocodone (pain)
ondansetron, tropisetron (pain)
Current AMP guidelines for pharmacogenetics takes into account VAF, the existence of ____________ material and testing ___________ feasibility
reference
testing feasibility
Both phase I enzymes ________ and _______ are on 10q23.3
CYPD26 and CYP2D19
The tier I alleles for CYP2C9 include *2, *3, *5, *8 and *11 that have ______ function while *6 has ______ function. This panel covers 75% of African ancestry.
decreased (function) = *2, *3, *5, *6, *8 and *11
No (function) = *6
The Tier 1 VKORC1*2 allele is a mutation in the ________ that results in reduced expression of the warfarin target and lower dosing requirement
promoter
For Tier 1 warfarin testing, which enzyme acts as the drug target?
VKORC1
