Download Lecture 3: Pharmacogenetics

Interpatient Variability of Drug
Response.
Genetic Factors
Pharmacogenetics
PGx chapter:
Website:
http://www.pharmgkb.org/
Pharmacogenomics tutorials
https://preview.pharmgkb.org/resources/education/tutorials.jsp
P- etics vs P-omics
PHARMACOGENETICS
• The study of how genes affect the way
people respond to drugs. Includes
examining genetic variation on drug
disposition, toxicity and efficacy. Single
gene-drug interaction.
PHARMACOGENOMICS
• The study of the role of genes & genetic
variations in the molecular basis of disease &
resulting pharmacological treatment of
disease. Full set of PK/PD genes examined.
More complex interactions.
DNA- Instruction Manual for the
Body
DNA strands are in a specific sequence of base pairs
(a 4-letter alphabet) to make words (genes).
GENE  mRNA  PROTEIN
Genes are responsible for “inherited or genetic traits
The order in which the bases are arranged is how DNA
information is transmitted to your body
Just like the order of the letters in a sentence, the
sequence of the DNA bases spells out instructions
When the letters are in the wrong deror or if
letters are skpped, the sentence may not make
sense to the body.
This results in genetic defects in the protein the
gene is responsible for making.
Genetic Variability
• Variations in genetic sequences frequently
occur between individuals.
• Most common is a single nucleotide
polymorphism within gene (SNP).
• If body is not able to “read”
DNA code- may result in abnormal proteins
and loss in function.
gactaagtcggTaactg…
gactaagtcggCaactg …
*10 million putative SNP locations in human genome
Classical PGx: Genetic Variation
in Drug Metabolizing Enzyme
Persons with SNP genetic defect in
enzyme resulting in poor
metabolism of drug
Metabolizing Enzyme
Build up of drug in blood and tissues
Altered Drug Response:
 Toxicity after Standard Doses
• For this course we will primarily
discuss single genetic traits affect
drug disposition and efficacy
(Pharmacogenetics)
• Functional polymorphic differences
have been discovered for numerous
genes which affect the PK and effects
of drugs. Includes genetic
polymorphisms of :
– Drug metabolizing enzymes
– Drug transporters
– Drug receptors
• Most polymorphs associated with
reduced activity of the protein.
• Associated with increased incidence
of toxicity or therapeutic failure in
patient population.
• Polymorphisms differ in frequency
among ethnic and racial groups.
Other terms
Allele: one of alternative genetic variants on
a single chromosome. A human has two
chromosomes, which may carry the same or
two different alleles.
Genotype: The specific genetic variants at
one or more loci of an individual.
Phenotype: Physical trait or characteristic
associated with genotype. eg. Enyzme
function
Polymorphisms: Genetic variations with a
frequency of >1% of the population. Gene
products exhibit altered activity in relation
to normal (wild type).
Single Nucleotide Polymorphism (SNP)substitution of a single nucleotide base.
History of PGx
Classical Pharmacogenetics An observation of abnormal drug
response
1950/60s
• Glucose-6-phosphate-dehydrogenase
– Severe anemia in some African-Americans
upon taking primaquine, later found in 400
million Africans.
• Isoniazid for tuberculosis
– Slow and rapid metabolizers, related to Nacetyltransferase variants.
• Unusually long anesethesia with
succinylcholine
– Prolonged effects due to atypical
cholinesterase
1960-70s
• Discovery that response to
debrisoquine (blood pressure
medicine) and opioids was related to
the level of CYP450 activity
• Later found to be CYP2D6, with many
(>80) polymorphisms in human
population
1970s:
• Analysis of clinical phenotypes related
to known genes
– E.g. hemoglobinopathies leading to sickle
cell anemia, thallesemia, clotting disorders
Genetic Variants
of Drug Metabolism
Polymorphic Genes
with Identified SNPs
Cytochromes P450
CYP2C9
CYP2D6
CYP2C19
Acetyltransferases
NAT2
Methyltransferases
TPMT
Dehydrogenases
DPD
ALDH
Sulfotransferases
SULT1A1
1) CYP 2D6
Involved in metabolism of 25% of all
therapeutic drugs (50 of top 100):
– dextromethorphan
– opioid analgesics
- codeine, hydrocodone...
– antidepressants
- SSRI
- tricyclic antidressants
– cardiac drugs
- -blockers
- debrisoquine
• Most recognized and characterized
polymorphism.
• Clinical consequences can be devastating.
1999
Prozac- Related Death of 9
Year Old Boy : Micheal AdamsConroy
Initially thought to be an intentional drug
overdose,
parents were charged with murder.
• 2nd Medical examination found that boy had a
genetic defect with the CYP2D6 drug
metabolizing enzyme.
• Genetic defect resulted in poor metabolism of
Prozac resulting in a toxic build up of his
prescribed Prozac dose…. eventually death.
May, 2006 Toronto Globe & Mail
Gene transforms drug into
morphine- kills infant of nursing
mother
• Newborn infant dies. While initially believed to be
SIDS, autopsy indicated death occurred due to
Morphine overdose.
• Nursing mother was prescribed routine doses of
codeine analgesic for episiotomy pain. Codeine
products are listed as compatible with breast
feeding.
• While codeine is normally converted to numerous
metabolites, Mother was found to carry multiple
genes of CYP2D6, which specifically transforms
codeine into morphine. Abnormal, toxic levels of
morphine were found in breast milk.
CYP 2D6 Polymorphisms
• Four phenotypes:
Poor (PM): two non functional alleles
Intermediate (IM): two fxn or 1 null & 1  fxn
Extensive (EM): at least 1 fully functional gene
Ultrarapid (UM): gene duplication
• PM frequency in North American:
(overall 5-10%)
– different frequency according to ethnicity
• UM frequency (CYP2D6*2xn)
–
–
–
–
–
–
Ethiopians: 16%
Saudi Arabian: 10.4%
Spaniards: 3.5%
Tanzanian: 3.0%
Caucasian- North American: 1-5%
Asian (Japanese & Chinese) : 1-2%
CYP2D6 Phenotypes
Frequency
in
Population
2D6 Enzyme Activity
High
to
Low
CYP2D6 Genotypes
*4, *5 – no enzyme
*10,*17 - enzyme
More than one SNP or allele associated
with altered enzyme function.
*2 in > 25% CA & AA (normal enzyme activity)
* 4 in 20% CA <10% AA (no enzyme activity)
*10 in > 70% Asians ( enzyme activity)
Examples of drugs metabolized by the
cytochrome P450 CYP2D6 enzyme
Tricyclic antidepressants
Amitriptyline
Clomipramine
Imipramine
Maprotiline
Desipramine
Nortriptyline
SSRI and atypical antidepressants
Fluvoxamine
Fluoxetine
Mianserin
Sertraline
Paroxetine
Venlafaxine
Antipsychotics
Clozapine
Haloperidol
Olanzepine
Perphenazine
Chlorpromazine
Risperidone
Opioid Analgesics
Codeine
Dextromethorphan
Hydrocodone Oxycodone
Ethylmorphine
Tramadol
Antiarrhythmics/ -blockers
Amiodarone
Flecainide
Proprafenone Carvedilol
Mexiletine
Timolol
Antiemetics
Dolasetron
Metoclopramide
Ondansetron
Anticancer
Doxorubicin
Lomustine
Tamoxifen
The Oncologist.
Interethnic Differences in Genetic Polymorphisms
of CYP2D6 in the U.S. Population: Clinical Implications
S. Bernard, K. Neville, A. Nguyen, D. A. Flockhart
CYP 2D6 PM
Clinical finding in PM:
• Lack of efficacy of opioid pro-drug products
– Codeine, tramadol, hydrocodone: efficacy
primarily due to active morphine ( or morphine
based metabolite) which is formed by CYP2D6.
– Reduced analgesia in PM
• High incidence of adverse effects with
CYP2D6 substrates, altered dose
requirements; rare serious adverse
reactions seen.
– Estimated that an ADR occurs in every
PM dosed with drug relying on CYP2D6
metabolism
CYP 2D6 UM
Ultrametabolizers
Altered Toxicity:
Clinical Report:
62 yr Male: codeine tid for cough. Loss of
consciousness on Day 4 (12 hr after last dose).
• ICU ventilation, miotic pupils, Glasgow coma
score 6.
• Morphine blood level 80 g/L (1- 4 g/L).
• Naloxone administered: awakened patient
• Genotype: > 3 functional 2D6 alleles
Altered Efficacy:
Therapeutic failure of Antidepressants
CYP2D6 Polymorphisms
and Nortriptyline PK
PM
IM
EM
UM
UM
Aus R. Weinshilboum: Inheritance and drug response,
New England Journal of Medicine 348, 529-537 (2003)
2) CYP 2C9
A woman was hospitalized for gastrointestinal
bleeding. Although she had been receiving only
warfarin 5 mg/day, her international normalized
ratio (INR) was 66. Warfarin was discontinued,
and her INR fell to 3.7 after transfusion of freshfrozen plasma. However, it rose again
spontaneously to 7.5. Eleven days after the last
dose of warfarin had been administered, it was
still detectable in the patient's plasma...
** Subsequent genotyping demonstrated
CYP2C9 SNP varient in patient
Bloch et al., Pharmacotherapy 22: 97-101, 2002
Polymorphic CYP2C9 and Warfarin
Sensitivity
Warfarin
• Anticoagulant
• Metabolized by CYP2C9
• Patients treated to effect
- Under-anticoagulation- thrombosis
- Over-anticoagulation-bleeding
• 50-fold variation in required dose
• CYP2C9*3 allele SNP (Ile359Leu)
results in 95% loss of enzyme function
• Homozygotes for CYP2C9*3 require
drastic reduction of warfarin dose
Polymorphic CYP2C9 and Phenytoin
toxicity
The study subject was a female African–
American presented to the emergency
department with phenytoin toxicity evidenced
by mental confusion, slurred speech, memory
loss and the inability to stand. She exhibited
extremely poor clearance of phenytoin with an
elimination half-life of 13 days.
Genotyping
demonstrated
CYP2C9
varient in
patient
Kidd et al., Pharmacogenetics 11: 803, 2001
CYP2C9 Polymorphisms
PM: *2 and *3 varients
Frequency of Polymorphisms:
 14-28% Heterozygotes (1*/3*)
Drug Clearances 40-70%
 0.2-1% Homozygotes (3*/3*)
Drug clearances < 25%
Drugs Metabolized by CYP2C9
S-Warfarin
NSAIDs / COX-2 inhibitors: Celecoxib, Naproxen,
Piroxicam, Diclofenac
Oral hypoglycemics:Tolbutamide, Glipizide, Glyburide
Sulfonylureas: Phenytoin, Tamoxifen, Floxetine,
Fluvastatin
3) CYP2C19
Originally identified as S-mephenytoin
hydroxylation polymorphism.
Numerous drugs metabolized by 2C19
Proton Pump Inhibitors: omeprazole
Anti-epileptics: diazepam, phenytoin, Smephenytoin, phenobarbitone
Tricyclic Antidepressants: amitriptyline,
imipramine
Warfarin
Nelfinavir
Poor Metabolizers:
Polymorphisms:
CYP2C19*2 & CYP2C19*3
Ethnic Differences
3-6% Whites
13-23% Asians
CYP2C19 PM Distribution
in Ethnic Groups.
ASIAN
15%
Caucasian
3%
Infection cure rate (%)
Clinical outcomes:
Effect of CYP2C19 genotype on H. pylori
infection cure rate after ulcer therapy with
omeprazole and amoxicillin
100
90
80
70
60
gastric
duodenal
50
40
30
20
10
0
wild-type
hetero
mutant
• Mutant (genetic varients) PMs have 6x higher AUC
of Omeprazole than wild-type.
• Mutant and hetero have longer duration of acid
suppression.
•
Require higher doses in wild-types?
Takahisa et al., Ann Int Med 129: 1027-1030, 1998
4) N- Acetyltransferase
•
Involved in the acetylation of several
drugs:
–
•
Caffeine, isoniazid, procainamide,
hydralazine, sulfamethazine, dapsone
Rapid and slow acetylators
Eskimos & Asians: 100% rapid
Egyptians : 20-40% rapid
North American (all races): 50% rapid
Clinical Impact:
Rapid Metabolizers
–
 hepatotoxicity with isoniazid
Slow Metabolizers
–
Serious adverse reactions
• Lupus reactions (hydralazine,
procainamide)
• Peripheral neuropathies (isoniazid)
5) Thiopurine methyltransferase
(TPMT)
• Metabolizes 6-mercaptopurine,
azathioprine
 6-MP is used in the treatment of childhood
leukemia.
• Incidence of decreased activity: 11%
• Incidence of deficiency: 0.3%
• Deficiency: profound bone marrow
depression
Example:
6-MP toxicity in TPMT genotypes
100
80
60
40
20
0
wild-type
hetero
mutant
- Children deficient in TPMT show marked 6-MP
toxicity
- Children with very high TPMT have therapeutic
failure
Mayo Clinic and St. Jude Children’s
Hospital now use prescreening tests for
TPMT variants to set 6-MP dose levels in
the treatment of childhood leukemia
•
6. Cytochrome P450 3A
• CYP3A4 / CYP3A5 responsible for
metabolism of approx 50-60% of
clinical used drugs.
• Account for 30% of hepatic CYP
P450 content.
CYP3A4 polymorphism
• Clinically important CYP3A4 genetic
variants have not yet been identified.
CYP3A5 polymorphism
– CYP3A5*3 allele non-functional
• Incidence: 82 % in Caucasians, 6.5% in
AA.
– CYP3A5*6 / *7 non-functional
• Incidence predominate in AA population.
B) Drug Transporters
MDR1 (ABCB1)
• Encodes for P-glycoprotein, an efflux
transporter
• Involved in distribution/elimination of
many clinically important drugs.
• Prevents or limits absorption of drugs
from GIT and entry of drugs into
CNS.
• Incidence of genetic varients and
impact on function not fully
characterized.
• MDR1 polymorphisms associated with
increased bioavailability of
fexofenadine and increased efficacy of
antiretroviral therapy in AIDS patients.
OATP1B1 (SLCO1B1)
- Encodes for organic anion transporter
- involved in cellular influx of endogenous &
exogenous anionic compounds.
- HMG-CoA reductase inhibitors (statins), steroids,
thyroid hormones, arachidonic acid metabolites
- Polymorphisms (activity)
- ↑ AUC of statins (pravastatin, atorvastatin,
rosuvastatin) due to  hepatocellular uptake &
clearance.
-  AUC fexofenedine & repaglinide due to 
intestinal uptake.
C) Drug Receptors.
Examples:
1) 2-adrenergic receptor SNP varients
– Frequency of polymorphism- 37% .
– Associated with lung function in
asthmatic patients.
–  response to 2-adrenergic agonist (ie.
Albuterol).
• Polymorphisms explains up to 20% of
variable response.
2) ApoE4 genotype
– Predictive of response to tacrine therapy
in Alzheimer’s disease.
– Absence: 84% success rate
– Presence: 40% success rate
Pharmacogenetic varients can be
distinguished according to the number of
genes responsible for the “phenotype”
• Most phenotypes identified to date (ie PM
vs EM) are Monogenic (due to allelic
mutations at a single gene locus)
– Initial pharmacogenetic examples are simple,
with one gene-one drug.
– Has been hard to find consistent associations
when examining a single SNP alone.
• Phenotypes based on variation of multiple
genes (Polygenic) are now being
examined.
– Increasingly being used to explain sources of
patient variability in disease and therapy.
– Associations of complex drug response with
genetic varients is where pharmacogenomics
is heading over the next 5-10 years.
Non-classical Polymorphisms
1) Non-coding promoter variants
– Influences basal expression or
induction of protein
UGT1A1*28
- Polymophism in TATA-box promoterr
region leads to  expression of
UGT1A1.
– UGT1A1*28 common in Caucasians
(10 - 40%) and is associated with a
significant decrease in UGT1A1
activity.
Clinical implication:
- Irinotecan: 4X ↑ in severe doselimiting toxicity in PM.
Ironotecan is activated to SN-38, which is
metabolized by UGT1A1
N
N O
N
O
O
Ironotecan
N
O
esterase
HO
N
HO
C2H 5 O
CYP3A4
O
N
O
HO
C2H5 O
SN-38
HO
UGT1A1
O
H
N
N O
O
N
O
N
O
HO
C2H5 O
COOH
O
O
HO
O
N
N
OH
O
HO
SN-38G
C2H5 O
Diarrhea associated with decreased
metabolism of SN-38 in patients
CPT-11
SN-38G
NO DIARRHEA
AUC Ratio
1:1
AUC
Ratio
7:1
DIARRHEA
SN-38
Gupta, Cancer Res, 1994
Active metabolite of SN-38 metabolized
by UGT1A1
Variability in metabolism of SN-38
associated with toxicity
MJR040902
counts(cells/ul)
cellnadir
White blood
ANC
Clinical Study :
Neutropenia correlated with
UGT1A1 *28 7 genotypes in
patients
7500
5000
No Gr 4
neutropenia
50%
incidence
of Gr 4
neutropenia
2500
0
5/6 6/6 6/7 6/8 7/7 7/8
UGT1A1 genotype
Nonparametric trend analysis among 6/6, 6/7, 7/7,
p<0.01
Revised Irinotecan (Camptosar®)
label (effective June 7th, 2005)
• Haplotypes
– A combination of alleles (DNA
polymorphisms) which are located
closely together on the same
chromosome and tend to be inherited
together.
• Combination of SNPs that are inherited in
blocks. Can be on different genes
Eg. VKORC1 haplotype and warfarin
(Vitamin K epoxide reductase complex)
- 10 common noncoding VKORC1 SNPs
found with five major haplotypes.
– Haplotype A associated with low dose
requirements.
– Haplotype B associated with high
dose requirements.
Pathways
– Interactive effects of several genes
in a pathway.
Example:
• Recently found that warfarin doses can be
better predicted by combining genotype
information for CYP2C9 (enzyme
responsible for its metabolism) and
haplotypes of its drug target, the Vitamin
K epoxide reductase complex 1
(VKORC1).
• FDA recommends revisions in warfarin
product label to include information about
polymorphisms of both CYP2C9 and
VKORC1
• Whole Genome Scans being used to
find complex associations between
genetic variation and response.
Genome-wide association studies
Gene Expression Response to
Cyclosporin and rhIL11 in Psoriasis
• 142 found to
associate with
improvement of
psoriatic skin in
response to
therapeutic
agents
• Gene expression
reflects drug
response
Avg. PSI
5.6 1
9
8.7
5.8
4.1
Avg. PSI 9.5
9.5
8
9
9
10
Fold Change
(lesion/treatment)
• 159 found to
associate with
psoriasis
Non-Responder
Responder
Fold Change
(lesion/treatment)
• Clinical Trial
Evaluated >7000
genes in
microarray
1
0.1
0.1
0
1
4
8
0
12
Treatment Week
Andrew J. Dorner
1
4
8
12
Treatment Week
Molecular Medicine,
Wyeth
Self-organizing map analysis of drug
response for psoriasis-related genes
Patient Individualization of Drug
Therapy based on Genetic Factors
• Virtually Nothing in Practice- Yet.
– Genotyping is a relatively new area.
– Few patients have information on their
genotype/phenotype.
– Research findings have not translated
into distinct dosage recommendations
for use in clinical practice.
– Primary strategy of Rx&D has been to
avoid marketing new drugs with
polymorphic characteristics.
• Advancement of methodologies and
services to genotype patients
• Pharmacist’s role in developing
drug/dosage strategies very
important
Individualization of Doses
in Patients with Genetic Varients
• Consider relative contribution of the
polymorphic enzyme to the total
elimination of the drug.
– ie. What % of CLT is it responsible for?
• Consider therapeutic index of drug.
• Use logic
Example:
SSRI drug cleared via CYP2D6 hepatic metabolism
(60%) and renal excretion (40%). CLT = 680
ml/min. IV dose of 5 mg/day gives therapeutic
plasma Css of 5.1 g/L.
– CYP2D6 enzyme responsible for 60% of total
drug clearance. [CLH = 408 ml/min]
– CYP2D6 *3/*3 SNP varient results in nonfunctional enzyme (0% activity, CLint = 0, CLH
= 0].
CLT = CLR + CLH = 272 ml/min (16.3 L/hr)
Css = Dose / τ* CLT  Dose / τ = Css * CLT
Dose = 5.1 g/L * 16.3 L/hr
= 83.1 g/hr
= 1.99 mg/day ~ 2.0 mg/day IV
Patients who are homozygotes for this nonfunctional SNP should receive 40% of normal IV
dose.
What if we are giving an oral dose? How
do we calculate the oral bioavailability
and hepatic first pass metabolism in
PM?
What if SNP mutation results in enzyme
with 50% function or if have one
functional and one non-functional gene
(IM)? (ie. Enzyme activity = 50%).
Will work on these types of dosage adjustment
calculations after we finish up lectures on dosage
adjustment based on variable hepatic function.
Clinically used Dosage
modifications
Based on PK principles, dosage
guidelines for antidepressant drugs
were recommended for CYP2D6
and CYP2C19 Genotypes. (Acta
Psychiatr Scand 2001; 104:173-92)
Dose change based on:
– Significant involvement of 2D6
or 2C19 in metabolism of drug.
– Clinical reports of significant
changes to Css & AUC in PM vs
EM
– Evidence of adverse events
– Evidence of therapeutic failure
Dosage Adjustment Calculations
• PK changes based on clinical reports in liter.
Review of AUC or Css in EM, IM & PM
n= AUCEM / AUCPM
m = AUCEM /AUCIM
• Genotype doses then calculated based on the
assumption that standard dose (DAv) recom. are based
on studies in genetically mixed populations. DAv
considered as weighted mean of Caucasian
population.
– CYP2D6 based on genotype frequency of: 10%
PM, 40% IM and 50% EM.
DEM (%)=
______100__________
( 0.1*n + 0.4*m + 0.5)
DPM (%) = n * DEM
DIM (%) = m * DEM
Dosage Guidelines
-Not ideal but 1st guidelines developed & made
publically available.
% Manufacturer’s Recommended Dose
(+++: no dosage adjustment necessary)
CYP 2D6 Phenotype
CYP 2C19 Phenotype
DRUG
Amitriptyline
Citalopram
Clomipramine
Desimpramine
PM
EM
PM
EM
50%
+++
60%
30%
120%
+++
120%
130% EM
260% UM
110%
120%
130%
130%
110% EM
300% UM
+++
60%
60%
70%
+++
110%
+++
+++
+++
+++
+++
60%
+++
+++
+++
+++
+++
+++
+++
40% 1st
60% MD
+++
110%
+++
+++
40%
???
110%
???
Non-linear PK
Fluoxetine
Fluvoxamine
Imipramine
Maprotiline
Mianserine
70%
60%
30%
40%
70%
Moclobemide
+++
Non-linear PK
Nortriptyline
50%
Paroxetine
20% 1st
70% MD
???
20%
Trimipramine
Venlafaxine
120% EM
230% UM
130% 1st
110% MD
???
130%
+++
Nomogram of dose estimates of
antidepressants based on
CYP2C19 Genotype
Recently found on Genelex® websitePM : require 40-70% of most of the antidepressants
IM: require 70-85%
Nomogram of dose estimates of
antidepressants based on
CYP2D6 Genotype
Recently found on Genelex® website.
PM : require 20-70% of most of the antidepressants
IM: require 75-85%
UM: require 100-200%
Netherlands:
Royal Dutch Assoc. for
Advancement of Pharmacy
• Established Pharmacogenetics Working Group
in 2005.
– 15 multidisciplinary “clinical” working group
– Objective to develop PGx based dose guidelines
(based on literature review) & integrate
recommendations into automated computer
medication prescribing/ surveillance programs.
1st recommendations released October 2006
- Examined 85 genotype/phenotype-drug
comprising 26 drugs. Assessed drugs were
primarily substrates of CYP2D6 (21/26).
- Therapeutic (dose) recommendations compiled
for 17 of 26 assessed drugs.
Calculation of Dose Adjustments
• PK changes based on clinical reports in
literature. Review of AUC, Css or oral CL
in EM, IM & PM
• Assumed that currently used standard doses
are representative for EM.
• Calculated dose adjustment for each
geno/phenotype based on each report using:
DPM (%) = [AUCEM / AUCPM ] *100 %
- Average mean of results used in final dose
adjustment recommendation.
Swen J et al. CPT, 2008 (PHM324 website)
DO NOT DISTRIBUTE
will not be published until June 2008.
Pharmacist’s Role
1) Interpretation of information
– When is it clinically relevant ?
• Recognize polymorphisms which
predisposes patients to toxic plasma conc,
toxic effects or are assoc. with inefficacy
(nonresponders).
– Assistance in Appropriate Prescribing
2) Patient Education
3) Assistance in Establishing Drug and
Dosage “Guidelines” for Genotype
Populations.
– Think about how you could estimate and
advise physicians on dosage changes in
patients with abnormal genotypes when no
published dosage recommendation are
available
• Unless “something can be done” from the
information obtained from the genetic
tests, there will be little clinical value in the
tests.
• Intervention by pharmacists – ‘drug
experts’ who are trained in
pharmacogenomics, pharmacokinetics
and individualization of drug therapy will be critical.
Data Sources
https://preview.pharmgkb.org/index.jsp
CYP P450 substrates:
http://medicine.iupui.edu.flockhart/
What will be the driving force for
pharmacogenetic testing?
Test prices start at $ 199.
Direct-to-Consumer Genetic Testing
Direct to consumer marketing of genetic testing (for
disease risk and pharmacogenetics) has begun.
Many are reaching consumers through the internet.
Gender/Sex
• Hormone effects
– affects fat distribution/ ratio
– altered drug metabolism ?
– Oral contraceptives-  CYP3A activity
Dextromethorphan Metabolite Ratios
in women at different stages of the
menstrual cycle.
Menstrual Metabolite Ratio
Phase
DX:DM
DM:3MM
Follicular
Luteal
Menses
Ovulatory
400
200
130
169
2.66
1.51
2.71
3.73
• CYP activity dependent on Menstrual Phase.