Title: Important Genotypes in DrugEnzyme Interactions
1Important Genotypes in Drug-Enzyme Interactions
- Nissa Abbasi-Shaffer
- University of Washington
- School of Pharmacy
- Doctoral Candidate, 2009
- August 1, 2008
2Outline
- Introduction
- Genotypes in GeneMedRx
- Additions to GeneMedRx
3Drug-Enzyme Interactions
- The activity an enzyme will have on a substrate
is determined in part by the physical
enzyme-substrate interaction - (Nonsynonymous) Mutations in genes can affect the
protein product interaction - Conformational changes
- pH changes
- H-bonding changes
- Patient response to drugs can be altered by their
genotype
4Genotypes in GeneMedRx
- Function in GeneMedRx for genotype selection
- Users can select appropriate genotype and
medication profile to determine if an
interaction exists - Metabolic enzymes
- Reduced efficacy eg. CYP2D6 UM
- Increased toxicity eg. CYP2C9 PM
- Target sites
- Efficacy eg. Her2/Neu
- Toxicity?
5Updated Genes
- CYP2D6
- CYP2C9
- CYP2C19
- NAT2
- TPMT
- UGT1A1
Each phenotype was given a descriptor so that if
selected, regardless of whether a known drug
interaction exists, the significance of the
genotype is displayed
6e.g. CYP2D6 Poor Metabolizer updated note
- Gene 2D6 Poor Metabolizer
- Cytochrome P450 2D6 Poor Metabolizers (PM) have
absent or greatly reduced CYP2D6 activity. They
are identified by DNA testing and comprise up to
12 of the population. Drugs that are substrates
of 2D6 will reach higher levels in 2D6 PMs and
may cause toxicity. The increase is often
substantial, roughly equal to adding a strong 2D6
inhibitor drug. Poor metabolizers may need to be
started at 20-60 of standard doses for drugs
metabolized by 2D6. - Prodrugs that require activation by CYP2D6 may be
less effective in PMs, including tamoxifen,
codeine, tramadol, risperidone and encainide. - Recommendations for 2D6 genotype-based changes in
dosage for many psychotropic drugs can be found
at http//www.healthanddna.com/professional/depre
ssion.html
7New Genotypes Added
- MTHFR
- DPYD
- HLA-B5701
- HER2/NEU
- 5HTT
8MTHFR
- Methylene tetrahydrofolate reductase is an
important enzyme in folate metabolism - Allows for methyl group transfer needed for DNA
synthesis and methylation - Reduced activity is associated with homocysteine
accumulation - Folate status may be associated with malignancy
(reduced -CH3) - Position C677T mutation results in
loss-of-function of reductase enzyme - T/T 70 reduction seen in 10 of North
Americans - C/T 40 reduction seen in 40 of North
Americans - One study reports 677T allele frequencies of
- Caucasians 0.34 Japanese 0.42 Africans 0.08
9Methotrexate
- Folate analog that inhibits dihydrofolate
reductase (also important in folate metabolism) - MTX used to treat many cancers, rheumatoid
arthritis psoriasis - T/T genotype associated with increased toxicity
- Fever, malaise, GI, skin, pharyngeal, pulmonary
- mucositis extended thrombocytopenia reported in
leukemia pts - Genotype is important in predicting response
10Folate pathway
MTX
Image downloaded from http//www.pharmgkb.org
11DPYD
- Dihydropyrimidine dehydrogenase is the initial
and rate-limiting enzyme in pyrimidine (uracil
thymine) catabolism - Exon 14-skipping mutation
- GT to AT mutation located in the 5-splicing
consensus sequence - Causes exon 14 of DPYD to be spliced out and not
expressed in protein product, DPD - 165 bp deletion 55 amino acids absent
- Complete loss-of-function
- Mutation found in 1 of European-based
population
12Fluorouracil
- Analog of uracil
- DPD is the initial enzyme in its metabolism
- Reduced DPD activity causes increase 5FU levels
- 5FU is widely used in cancer therapy (breast,
colon, head neck, etc.) - Toxicity from 5FU is reported to occur in those
who have even 50 of DPD activity--one null
allele can be enough - Toxicity can be severe, including mucositis,
granulocytopenia - In one study 24 of patients with WHO grade IV
toxicity were found to have the exon 14-skipping
mutation - PM will need dose reduction
13HLA-B5701
- The HLA class I molecules present antigens to
killer T cells to induce immunity - Some allotypes within this class have a
propensity to induce allergic-type reactions - The HLA-B5701 genotype is associated with
allergic reactions to abacavir - Found in 5 of the European-based population
(less common in African Americans) - Abacavir Hypersensitivity Syndrome (AHS)
- Graft vs host-like response, generally appears
within 6 wks - Symptoms can include rash, fever, malaise,
nausea, vomiting, diarrhea, respiratory problems,
and can be fatal - A reaction requires immediate discontinuation of
the drug do not rechallenge
14FDA Alert
Last week (7/24/2008) the FDA issued an alert
recommending all patients be genotyped before
starting or restarting abacavir due to the high
correlation of AHS to this drug, the potential
severity of the symptoms and the ease of
preventing the reaction by DNA testing.
15HER2/Neu
- HER2 belongs to the Epidermal Growth Factor
Receptor family, associated w/ cellular growth
and differentiation - Overexpression of the HER2 protein found in
18-20 of breast cancer resulting in more
aggressive tumors - Clinical testing (IHC and FISH) to screen
overexpressors - determines course of therapy targeted or not
- better response to anthracyclines
- Current targeted therapies
- Trastuzumab (Herceptin) efficacy associated w/
overexpressionstd treatmant for early stage
Her2/Neu positive breast cancer (given in combo
w/ chemo) - Lapatinib is an oral TKI targeted to Her2/Neu in
patients who are overexpressors who failed
Herceptin therapy (given in combo with
capecitabine)
165HTT/SLC6A4
- The serotonin transporter (5HTT) reuptakes
serotonin from the synaptic cleft into the
presynaptic terminus - 5HTT is the target of SSRIs--limiting reuptake
allows for more serotonin transmission - Variability in SSRI efficacy within the general
population has lead the search for a genetic
explanation - Discovery of 5HTTLPR polymorphism
175HTTLPR
- The serotonin transporter-linked polymorphic
region is located in the promoter region of 5HTT - 44-bp insertion/deletion produces the long (L
16 repeat units) and short (S 14 repeat units)
alleles - S allele results in 50 of the transcriptional
activity as the L allele - 40 of North Americans carry at least one S
allele (varies from 10-70 globally) - Other lengths have been discovered, but very rare
in the population 15, 18-20, 22 repeated units - S allele is associated with reduced efficacy to
SSRIs - Hypothesis if less transporter made, less target
for SSRIs - Carriers of the S allele often take longer to
respond or do not respond at all - Genotyping can be used to identify candidates
18- Thank you Genelex!
- Any questions???
19References
- MTHFR
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ethnic differences in allele frequencies of
single-nucleotide polymorphisms in the
methylenetetrahydrofolate reductase gene and
their influence on response to methotrexate in
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Sep65(9)1213-8 - Frosst P, Blom HJ, Milos R, Goyette P, Sheppard
CA, Matthews RG, Boers GJ, den Heijer M,
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