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Important Genotypes in Drug- Enzyme Interactions Nissa Abbasi-Shaffer University of Washington School of Pharmacy Doctoral Candidate, 2009 August 1, 2008.

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Presentation on theme: "Important Genotypes in Drug- Enzyme Interactions Nissa Abbasi-Shaffer University of Washington School of Pharmacy Doctoral Candidate, 2009 August 1, 2008."— Presentation transcript:

1 Important Genotypes in Drug- Enzyme Interactions Nissa Abbasi-Shaffer University of Washington School of Pharmacy Doctoral Candidate, 2009 August 1, 2008 Nissa Abbasi-Shaffer University of Washington School of Pharmacy Doctoral Candidate, 2009 August 1, 2008

2 Outline Introduction Genotypes in GeneMedRx Additions to GeneMedRx Introduction Genotypes in GeneMedRx Additions to GeneMedRx

3 Drug-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 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

4 Genotypes 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? 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?

5 Updated Genes CYP2D6 CYP2C9 CYP2C19 NAT2 TPMT UGT1A1 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

6 e.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: 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:

7 New Genotypes Added MTHFR DPYD HLA-B*5701 HER2/NEU 5HTT MTHFR DPYD HLA-B*5701 HER2/NEU 5HTT

8 MTHFR 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 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

9 Methotrexate 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 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

10 Folate pathway Image downloaded from MTX X X

11 DPYD 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 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

12 Fluorouracil 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 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

13 HLA-B*5701 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-B*5701 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 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-B*5701 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

14 FDA 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.

15 HER2/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/ overexpression std 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) 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/ overexpression std 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)

16 5HTT/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 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

17 5HTTLPR 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 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??? Thank you Genelex! Any questions???

19 References MTHFR: Kremer JM. Methotrexate pharmacogenomics. Ann Rheum Dis Sep;65(9): Hughes LB, Beasley TM, Patel H, et al.Racial or ethnic differences in allele frequencies of single-nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene and their influence on response to methotrexate in rheumatoid arthritis. Ann Rheum Dis Sep;65(9): Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.Nat Genet May;10(1):111-3 DPYP: Tomalik-Scharte D, Lazar A, Fuhr U, Kirchheiner J. The clinical role of genetic polymorphisms in drug- metabolizing enzymes. Pharmacogenomics J Feb;8(1):4-15 Maitland ML, Vasisht K, Ratain MJ. TPMT, UGT1A1 and DPYD: genotyping to ensure safer cancer therapy? Trends Pharmacol Sci Aug;27(8):432-7 Wei X, McLeod HL, McMurrough J, Gonzalez FJ, Fernandez-Salguero P. Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity. J Clin Invest Aug 1;98(3): HLA-B*5701: Saag M, Balu R, Phillips E, et al; Study of Hypersensitivity to Abacavir and Pharmacogenetic Evaluation Study Team. High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. Clin Infect Dis Apr 1;46(7): Mallal S, Phillips E, Carosi G, et al; PREDICT-1 Study Team. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med Feb 7;358(6): Chessman D, Kostenko L, Lethborg T, et al. Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity. Immunity Jun;28(6): HER2/Neu: Lin A, Rugo HS.The role of trastuzumab in early stage breast cancer: current data and treatment recommendations. Curr Treat Options Oncol Feb;8(1): Yamauchi H, Hayes D. HER2 and predicting response to therapy in breast cancer. Downloaded from: [accessed 2008 July 29]. 5HTT: Lesch KP, Gutknecht L. Pharmacogenetics of the serotonin transporter. Prog Neuropsychopharmacol Biol Psychiatry Jul;29(6): Gelernter J, Cubells JF, Kidd JR, Pakstis AJ, Kidd KK. Population studies of polymorphisms of the serotonin transporter protein gene. Am J Med Genet Feb 5;88(1):61-6. Heils A, Teufel A, Petri S, Stöber G, Riederer P, Bengel D, Lesch KP. Allelic variation of human serotonin transporter gene expression. J Neurochem Jun;66(6): MTHFR: Kremer JM. Methotrexate pharmacogenomics. Ann Rheum Dis Sep;65(9): Hughes LB, Beasley TM, Patel H, et al.Racial or ethnic differences in allele frequencies of single-nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene and their influence on response to methotrexate in rheumatoid arthritis. Ann Rheum Dis Sep;65(9): Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.Nat Genet May;10(1):111-3 DPYP: Tomalik-Scharte D, Lazar A, Fuhr U, Kirchheiner J. The clinical role of genetic polymorphisms in drug- metabolizing enzymes. Pharmacogenomics J Feb;8(1):4-15 Maitland ML, Vasisht K, Ratain MJ. TPMT, UGT1A1 and DPYD: genotyping to ensure safer cancer therapy? Trends Pharmacol Sci Aug;27(8):432-7 Wei X, McLeod HL, McMurrough J, Gonzalez FJ, Fernandez-Salguero P. Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity. J Clin Invest Aug 1;98(3): HLA-B*5701: Saag M, Balu R, Phillips E, et al; Study of Hypersensitivity to Abacavir and Pharmacogenetic Evaluation Study Team. High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. Clin Infect Dis Apr 1;46(7): Mallal S, Phillips E, Carosi G, et al; PREDICT-1 Study Team. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med Feb 7;358(6): Chessman D, Kostenko L, Lethborg T, et al. Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity. Immunity Jun;28(6): HER2/Neu: Lin A, Rugo HS.The role of trastuzumab in early stage breast cancer: current data and treatment recommendations. Curr Treat Options Oncol Feb;8(1): Yamauchi H, Hayes D. HER2 and predicting response to therapy in breast cancer. Downloaded from: [accessed 2008 July 29]. 5HTT: Lesch KP, Gutknecht L. Pharmacogenetics of the serotonin transporter. Prog Neuropsychopharmacol Biol Psychiatry Jul;29(6): Gelernter J, Cubells JF, Kidd JR, Pakstis AJ, Kidd KK. Population studies of polymorphisms of the serotonin transporter protein gene. Am J Med Genet Feb 5;88(1):61-6. Heils A, Teufel A, Petri S, Stöber G, Riederer P, Bengel D, Lesch KP. Allelic variation of human serotonin transporter gene expression. J Neurochem Jun;66(6):


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