Class Slides

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With much content shamelessly pilfered from Dr.
DeFranco’s lecture slides on pharmacogenetics….
PHARMACOGENOMICS
Jennifer Hu
CoSBBI, July 12 2013
A FEW QUESTIONS TO GET US STARTED…
What is pharmacogenomics?
 What is pharmacogenetics?
 How do (most) clinical drug trials work?
 Name some factors that are currently taken into
consideration when prescribing drugs…
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PHARMACOGENOMICS VS.
PHARMACOGENETICS
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Pharmacogenetics focuses on variation in one or a few genes
Pharmacogenomics uses genome-wide information to predict
drug response.
What factors do we consider now when prescribing drugs?
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Age
Gender
Weight
Therapeutic drug monitoring
Organ function
Future goal: personalized medicine! Give the right drug to
the right patient at the correct dosage. (The assigned
reading provides many examples of how things can go
terribly awry if genetic factors are not taken into
consideration.)
Need for companion diagnostic tests!
Ideas about what questions that we’d want to answer?
WHICH GENES MIGHT BE IMPORTANT?
Pharmacokinetic (PK) genes: absorption,
distribution, metabolism, and excretion.
 Pharmacodynamic (PD) genes: direct targets
themselves, genes affected downstream, and the
genes responsible for the clinical outcome.
 Now you should be able to correctly answer the
question on the pretest: “The sites for genetic
variations that might affect drug response
include…”
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AN EXAMPLE OF PHARMACOKINETIC GENE
INTERACTIONS: LIVER DRUG METABOLIZING
ENZYMES
Phase I: oxidation, reduction, hydrolysis etc.
Major system is cytochrome P450 (CYP) enzymes
 Phase II: conjugating enzymes (acetylation,
glucuronidation, glutathionation, sulfation)
 Metabolizing reactions transform drugs into
more water soluble forms to aid in their
elimination
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SOME DRUG METABOLIZING ENZYMES SHOWING
CLINICALLY SIGNIFICANT VARIATION
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CYP2D6
 Role in metabolizing ¼ of all prescription
drugs currently on the market
Anti-depressants (SSRIs, tricyclics)
 Anti-psychotics
 b-blockers; some anti-arrhythmics
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CYP2C9
 Warfarin (Coumadin®)
UGT1A1
 Irinotecan (Camptosar®)
CASE
22 year old woman with symptoms suggesting
depression. Her primary care physician
prescribes venlafaxine (Effexor®). This is an
SSRI.
 As an aside, what are symptoms of depression?
 10 days later, the patient presents with
complaints of racing heart rate and confusion.
 The physician questions whether she has taken
codeine in the past. (WHY?)
 She says she was prescribed
codeine/acetaminophen (Tylenol 3) after routine
surgery 5 years ago and did not get pain relief.
Morphine, however, was effective at that time.
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QUESTIONS FOR CASE
What are possible explanations for the patient’s
symptoms?
 What about the reported history of
ineffectiveness of codeine but effectiveness of
morphine?
 …. Also, since we are talking about drug
metabolizing enzymes, which one is the suspect
here?
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What are possible explanations for the
patient’s symptoms?
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Overdose of drug (intentional or inadvertent)
Low activity of CYP2D6 due to genetic
variation (poor metabolizer) or the patient may
be taking another drug which inhibits CYP2D6
activity
Liver failure
 What
about the reported history of
ineffectiveness of codeine but
effectiveness of morphine?
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Codeine is a pro-drug that needs to be
converted to morphine (mainly by CYP2D6)
With low CYP2D6 activity, codeine will not be
converted to morphine
In a Canadian study, there were no poor
metabolizers in a population of several
hundred codeine addicts
 No conversion to morphine means no
euphoric effects
So, what happened was likely that her
metabolism of drug was slower than average 
adverse drug reaction with standard dose
 Poor metabolizer! Two copies of low or null
activity gene.
 There are also ultra-rapid metabolizers (usually
due to gene multiples), extensive metabolizers
(normal), and intermediate metabolizers.
 Another note that may be of interest- the tragic
tale of CYP2D6 ultra-rapid metabolizers and
their breast-fed children
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AN EXAMPLE OF PHARMACODYNAMIC
INTERACTIONS: WARFARIN
Warfarin (coumadin) is a commonly prescribed
oral anti-coagulant.
 Common cause of adverse drug reactions: too
much drug results in increased bleeding, too little
results in inadequate anti-coagulation (leading to
possible stroke, DVT etc.)
 Need for monitoring
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Drug target: vitamin K
epoxide reductase complex
subunit 1 (VKORC1 or
VKOR)
Vit K needs to be converted
from inactive epoxidized
form to active reduced form
Warfarin binds to VKORC1
near its catalytic site,
inhibiting the reduction
reaction.
VKORC1 variants are
associated with warfarin
resistance in humans
Clotting cascade
BRIEF AND INCOMPLETE OVERVIEW OF
DRUG-RECEPTOR INTERACTIONS
What is an agonist?
 What is a partial agonist?
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What is an antagonist?
 What is an competitive antagonist?
 What is a non-competitive antagonist?
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SOME DEFINITIONS…
Potency – A measure of the
amount of ligand (drug)
needed to produce an effect
of an given magnitude (i.e.
ED50).
 Efficacy – The effectiveness
of a ligand or drug when
eliciting a biological
response.
 Is drug X or drug Z more
potent?
 Is drug X or drug Y more
efficacious?
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Agonist – A compound (drug) that binds to a
receptor and produces a biological effect that
mimics the endogenous ligand
 Partial agonists have efficacy greater than 0 but
less than that of a full agonist
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Antagonist – A compound (drug) that binds to a
receptor and blocks the action of its endogenous
ligand or other agonists.
 Competitive antagonist
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Binds to the same site as the agonist
2. Doesn’t change the maximum response of an agonist but
decreases its potency (i.e. right shift of dose response curve)
3. Competitive antagonism is surmountable at high enough
concentrations of the agonist
1.
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Non-competitive antagonist
1.
2.
3.
Bind to the same site as the agonist but dissociate so slowly
to essentially irreversibly block agonist binding or bind to a
distinct site (allosteric antagonist) and block agonist binding.
The potency of an agonist won’t be affected but its maximum
response will be reduced.
Effects are non-surmountable by increasing agonist
concentraion
Now you should be able to answer the question:
“For a competitive antagonist, all of the following
are correct EXCEPT:…”
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DISCOVERY OF PHARMACOGENOMIC GENES
AND VARIANTS
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Association Methods
GWAS for SNPs (What is a SNP?)
 Chi square or Fisher’s exact test for association between SNP and
trait*
 LR for continuous independent variable*
 Correct for multiple comparisons. WHY?
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Expression Methods
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RNA expression data from microarrays or RNA-Seq experiments
from drug-treated samples
Cheminformations/NLP
Combining information about protein structure and small molecule
structure, docking methods predict the best fit of a molecule
 Alternatively, if a given molecule is previously known to interact
with a protein, molecule similarity metrics can be included to
suggest similar molecules as protein-binding candidates.
* We will do an example question at the end if there’s time…
Also note that GWAS will be covered on July 17.
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WHAT HAPPENS NEXT…?
Pathway discovery
 Validation: measuring binding affinity or
functional assays
 Clinical trial!
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