Flashcards in Genetic Variations in Individuals and Populations Deck (71):
Optimizing drug therapies in the face of genetic variation
Pharmacogenetics and pharmacogenomics
The study of inherited differences (variation) in drug metabolism and response
Genetic variability can affect
Pharmacokinetics and pharmacodynamics
Clearance/excretion, metabolism, transportation, and absorption of drug
Drug activity and interaction with downstream targets
A 'genomic' approach to pharmacogenetics --using GWAS to assess the impact of an ensemble of SNPs on the impact of drug therapy
Genome wide association study
Single nucleotide polymorphism
How do we find the international normalized ratio (INR)?
INR = PTobs / PTnormal
PT = Prothrombin time
What is the normal Prothrombin Time (PT)?
56 enzymes, each encoded by a separate gene. All are heme-containing proteins expressed primarily in the liver. Responsible for detoxifying and exporting both endogenous and xenobiotic compounds
Cytochrome P450 (CYP)
CYP's can also activate
Accept electrons from donors such as NADPH to catalyze a number of different reactions, most importantly the addition of oxygen to C, N, or S atoms
Phase I of drug metabolism by CYP is
Hydroxylation of molecule
Functionalization of the hydroxyl group by a sugar or acetyl group, increasing drug solubility and allowing it to be excreted
Phase II of drug metabolism by CYP
Which CYPs react with Xenobiotics?
CYP 1, 2, and 3
Six genes in particular: CYP1, CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 are responsible for the metabolism of 90% of commonly used
Which is the most active CYP in common drug metabolism?
Used in the prevention of thrombosis, embolism in cases of heart valve prosthesis, recurrent stroke, DVT, and pulmonary embolism
-2 million prescriptions per year
Impairs the synthesis of vitamin K dependent clotting factors
Warfarin inhibits a key enzyme in vitamin K recycling called
Vitamin K Epoxide Reductase
How many major sites of modification by CYPs are there on warfarin?
Five (C's 4, 6, 7, 8, and 10)
Warfarin metabolized in the liver cell by C7 hydroxylation or C6 hydroxylation by CYP2C9
There is significant variation in the individual activity levels of
Is the CYP2C9 interaction with warfarin considered a component of Pharmacokinetics or Pharmacodynamics?
The action of drugs in the body over a period of time, including the processes of absorption, distribution, and localization in tissues
Classified as poor, normal, or ultrafast metabolizers
Which CYP2C9 variant has a 25% dose reduction?
Which CYP2C9 variant has a 35% dose reduction?
What is the recommended target therapeutic range for INR?
INR = 2.0 - 3.0
CYP variants are classified as
Poor (PM), Normal (intermediate, IM), or Ultrafast (extensive, EM) metabolizers
In the CYP2C9 family, what is an extensive metabolizer?
Wild type: CYP2C9*1*1
In the CYP2C9 family, what are intermediate metabolizers?
*1*2 and *1*3 variants
In the CYP2C9 family, what are poor metabolizers?
*2*2, *2*3, and *3*3 variants
Vitamin K epoxide reductase (gene: VKORC1) is a target of
Inhibition of VKORC1 by warfarin prevents regeneration of reduced vitamin K, which is necessary for gamma glutamyl carboxylation of
Prevents regeneration of reduced vitamin K, which is necessary for gamma glutamyl carboxylation of coagulation factors
Inhibition of VKORC1 by warfarin
Single nucleotide polymorphisms (SNPs) in VKORC1 correlate with
Is the VKORC1 interaction with warfarin considered a component of pharmacokinetics or pharmacodynamics?
Deals with drug activity and interaction with downstream targets
Combinations of alleles or genetic markers which occur more or less frequently than expected at random
Account for approximately 30% of variation in Warfarin sensitivity
VKORC1 + CYP2C9
Accounts for another 1-2% of warfarin sensitivity (according to a GWAS study of 2000 patients)
SNPs in CYP2C18 and CYP2C19 also correlate with a
Codeine intoxication is associated with ultra-rapid
A study found that there are 3+ copies of the CYP2D6 allele, which indicates
It was then found that naturally occurring variation in CYP3A4 has no observable effect on
Optimal codeine dosage
The combination of the gene duplication in CYP2D6 and the natural variation in CYP3A4 resulted in ultra-rapid conversion of codeine to
-10%converted by CYP2D6
-80% cleared by CYP3A4
Have provided valuable data in the areas of pharmacogenetics and pharmacogenomics. This is especially the case for adverse drug reactions attributable to alleles of a single gene, often one that encodes an enzyme contributing to metabolism of the
What are some of the factors that have limited GWA studies to date?
Sample size, phenotypic characterization, replication of findings, and effect size
Encodes the main metabolizing enzyme for coumarin anticoagulants such as Warfarin
Markers in which two genes are the main predictors for coumarin dosage?
VKORC1 and CYP2C9 genes
Accounts for approximately 1.5% of warfarin dosage variability
When a higher dose is required for therapeutic affect
When a lower dose is required for therapeutic affect
Has nothing to do with the mechanism of action of the drug.
-Just tells us how well the drug gets to its target
Tells us about the drugs activity and how well it interacts with its downstream targets
Tells us how quickly our blood clots
Prothrombin time (PT)
The therapeutic window is an INR of 2-3, below the therapeutic window, the drug is not helpful. Above the therapeutic window, the drug is
CYPs are mostly expressed in the
CYPs can activate drugs, an example of this is the activation of codeine to morphine by
The conversion of acetometophin to N-Acetyl-P-Benzoquinone imine by CYP3A4 is an example of how CYPs can be
We are given a racemic mixture of Warfarin, but which isomer is more active?
Processed by CYP2C9 into 7-hydroxywarfarin or 6-hydroxywarfarin
Multi-drug transporters that will push all xenobiotics out of the cell
An example of pharmacokinetics because it deals with how the drug is distributed and how it is processed
CYP2C9 interaction with Warfarin
The safe therapeutiv window represents
An Arg-->Cys mutation that results in reduced affinity for P450 reductase, which makes you more sensitive to Warfarin
-requires 25% lower dosage
An Ile-->Leu mutation that alters substrate specificity of CYP2C9 and will make you more sensitive to Warfarin
-requires 35% lower dosage