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University of Washington
1.
Henderson, Lindsay Maritza.
Impact of Warfarin Pharmacogene Variation on Drug Metabolism and Pharmacological Response in Alaska Native and American Indian Populations.
Degree: PhD, 2019, University of Washington
URL: http://hdl.handle.net/1773/44879 
► The oral vitamin K antagonist warfarin (Coumadin®) is used to prevent stroke in patients with atrial fibrillation and for secondary prevention of venous thromboembolism. Despite…
(more)
▼ The oral vitamin K antagonist warfarin (Coumadin®) is used to prevent stroke in patients with atrial fibrillation and for secondary prevention of venous thromboembolism. Despite newer treatment options such as the direct oral anticoagulants, warfarin remains a mainstay in anticoagulation therapy. Warfarin therapy requires intensive monitoring and dose titration due to its narrow therapeutic index and wide inter-individual response, due in part to genetic variation, as well as clinical, demographic, and environmental factors. While variation in VKORC1, CYP2C9, CYP4F2 and GGCX genes have been associated with the warfarin dose required to achieve a therapeutic anticoagulation response, these findings are based largely on variant alleles and their frequencies found in populations largely of European descent, and may not be generalizable to other, less studied populations such as Alaska Native and American Indian (AN/AI) people. It is important to characterize the unique genetic variation that exists in the AN/AI population because there are clinical implications of having uncharacterized genetic variation (eg, phenotype misclassification), particularly with drug metabolizing enzymes and drug target proteins. The projects described in this dissertation proposal inform on personalized warfarin therapy for AN/AI patients living in remote communities of Alaska and investigate the missing heritability in warfarin dose variance. Chapter 2 and 3 describe the in vitro and in vivo characterization of novel variation in CYP2C9 found in the indigenous population of Alaska. In Chapter 4, the impact of CYP2C9, VKORC1, CYP4F2, CYP4F11, and GGCX gene variation on stable warfarin dose was determined in an AN/AI population living in Southcentral Alaska. Chapter 5 seeks to better understand the variability in warfarin dose through a pathway-based analysis identifying potential regulators of VKORC1 that influence VKOR expression, and therefore warfarin dose requirement. This dissertation research has improved our understanding of the clinical relevance of VKORC1 as a determinant of therapeutic warfarin dose requirement in AN/AI people as well as the pharmacokinetic impact of novel CYP2C9 variation on warfarin metabolism and pharmacological response, in addition to other narrow therapeutic index CYP2C9 substrates. Overall, this data can be used to implement population-specific genetic variation in clinical decisions associated with personalized or precision medicine, and to assess whether pharmacogenetic testing provides unique advantages in rural AN/AI communities.
Advisors/Committee Members: Thummel, Kenneth E (advisor).
Subjects/Keywords: Alaska Native; American Indian; CYP; pharmacogenetics; precision medicine; warfarin; Pharmaceutical sciences; Pharmaceutics
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APA (6th Edition):
Henderson, L. M. (2019). Impact of Warfarin Pharmacogene Variation on Drug Metabolism and Pharmacological Response in Alaska Native and American Indian Populations. (Doctoral Dissertation). University of Washington. Retrieved from http://hdl.handle.net/1773/44879
Chicago Manual of Style (16th Edition):
Henderson, Lindsay Maritza. “Impact of Warfarin Pharmacogene Variation on Drug Metabolism and Pharmacological Response in Alaska Native and American Indian Populations.” 2019. Doctoral Dissertation, University of Washington. Accessed April 16, 2021.
http://hdl.handle.net/1773/44879.
MLA Handbook (7th Edition):
Henderson, Lindsay Maritza. “Impact of Warfarin Pharmacogene Variation on Drug Metabolism and Pharmacological Response in Alaska Native and American Indian Populations.” 2019. Web. 16 Apr 2021.
Vancouver:
Henderson LM. Impact of Warfarin Pharmacogene Variation on Drug Metabolism and Pharmacological Response in Alaska Native and American Indian Populations. [Internet] [Doctoral dissertation]. University of Washington; 2019. [cited 2021 Apr 16].
Available from: http://hdl.handle.net/1773/44879.
Council of Science Editors:
Henderson LM. Impact of Warfarin Pharmacogene Variation on Drug Metabolism and Pharmacological Response in Alaska Native and American Indian Populations. [Doctoral Dissertation]. University of Washington; 2019. Available from: http://hdl.handle.net/1773/44879
University of Washington
2.
Dorfman, Elizabeth Howard.
Translational Research in Obstetric Pharmacology: Historical Trends, Prenatal Pharmacogenomics, and an Opportunistic Study of Placental ABCG2 and Fetal Glyburide Exposure.
Degree: PhD, 2015, University of Washington
URL: http://hdl.handle.net/1773/34161
► This dissertation is principally comprised of three distinct but related projects. The first is an assessment of the quantity and nature of obstetric pharmacology clinical…
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▼ This dissertation is principally comprised of three distinct but related projects. The first is an assessment of the quantity and nature of obstetric pharmacology clinical trials conducted in the past decade, as well as a comparison of these trials to non-obstetric trials, in order to identify whether the challenges and complexities of conducting research in this field are reflected in the aggregate study data available through ClinicalTrials.gov. The analysis identified several significant differences between obstetric and non-obstetric trials, which have implications for program planning and funding needs. Second is an overview of the ways in which the fetal genome may be informative of fetal outcomes with regard to medication and other chemical exposures during pregnancy, and the attendant research prioritization of this area and clinical testing opportunities made possible by non-invasive prenatal genetic tests that utilize cell-free fetal DNA in a pregnant woman’s blood. Finally, an opportunistic clinical study was conducted, assessing whether fetal genotype for the placental efflux transporter breast cancer resistance protein (BCRP, ABCG2) is predictive of relative fetal exposure to the oral hypoglycemic agent glyburide, which is used, off-label as an alternative to insulin, to treat gestational diabetes. The results of the study showed no association between fetal ABCG2 Q141K genotype and relative glyburide exposure at term, which was unexpected given the extensive, albeit indirect, supporting evidence that formed the basis of the initial hypothesis. This result has clinical implications related to the optimal use of glyburide to treat gestational diabetes, and also underscores the complexity of drug disposition during pregnancy and the need to study pregnant women directly.
Advisors/Committee Members: Thummel, Kenneth E (advisor).
Subjects/Keywords: ABCG2; breast cancer resistance protein; fetal drug exposure; glyburide; obstetric pharmacology; placental drug transport; Genetics; Pharmacology; Obstetrics and gynecology; public health genetics
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APA (6th Edition):
Dorfman, E. H. (2015). Translational Research in Obstetric Pharmacology: Historical Trends, Prenatal Pharmacogenomics, and an Opportunistic Study of Placental ABCG2 and Fetal Glyburide Exposure. (Doctoral Dissertation). University of Washington. Retrieved from http://hdl.handle.net/1773/34161
Chicago Manual of Style (16th Edition):
Dorfman, Elizabeth Howard. “Translational Research in Obstetric Pharmacology: Historical Trends, Prenatal Pharmacogenomics, and an Opportunistic Study of Placental ABCG2 and Fetal Glyburide Exposure.” 2015. Doctoral Dissertation, University of Washington. Accessed April 16, 2021.
http://hdl.handle.net/1773/34161.
MLA Handbook (7th Edition):
Dorfman, Elizabeth Howard. “Translational Research in Obstetric Pharmacology: Historical Trends, Prenatal Pharmacogenomics, and an Opportunistic Study of Placental ABCG2 and Fetal Glyburide Exposure.” 2015. Web. 16 Apr 2021.
Vancouver:
Dorfman EH. Translational Research in Obstetric Pharmacology: Historical Trends, Prenatal Pharmacogenomics, and an Opportunistic Study of Placental ABCG2 and Fetal Glyburide Exposure. [Internet] [Doctoral dissertation]. University of Washington; 2015. [cited 2021 Apr 16].
Available from: http://hdl.handle.net/1773/34161.
Council of Science Editors:
Dorfman EH. Translational Research in Obstetric Pharmacology: Historical Trends, Prenatal Pharmacogenomics, and an Opportunistic Study of Placental ABCG2 and Fetal Glyburide Exposure. [Doctoral Dissertation]. University of Washington; 2015. Available from: http://hdl.handle.net/1773/34161
University of Washington
3.
Yracheta, Joseph Manuel.
A Comparison, Evaluation and Accuracy Assessment of the Fluidigm (TM) Platform in Genotyping Common and Rare variants in an Alaska Native Population.
Degree: 2014, University of Washington
URL: http://hdl.handle.net/1773/25335
► <underline>A Comparison, Evaluation and Accuracy Assessment of the Fluidigm (TM) Platform in Genotyping Common and Rare variants in an Alaska Native Population</underline> by Joseph Yracheta…
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▼ <underline>A Comparison, Evaluation and Accuracy Assessment of the Fluidigm
(TM) Platform in Genotyping Common and Rare variants in an Alaska Native Population</underline> by Joseph Yracheta Pharmacogenomics is a new and related addition to the battle in combatting health disparity. In American Indian and Alaska Native populations this battle comes with many practical, legal and bioethical constraints. The selection of study design, a tribal consultation process & partnership and genomic technology is crucial to avoid the bioethical missteps of the past. Here, we evaluate the Fluidigm platform in its performance against other genotyping platforms and its performance in the tribal consultation process. Fluidigm demonstrated comparable accuracy and reliability characteristics with other platforms and was superior in terms of flexibility, cost and assay time. These last three characteristics makes it more amenable for tribal consultation and approval processes.
Advisors/Committee Members: Thummel, Kenneth E (advisor).
Subjects/Keywords: Alaska Native; American Indian; Genomic Technology; Health Disparity; Pharmacogenomics; Vulnerable Populations; Genetics; Pharmaceutical sciences; Ethics; pharmaceutics
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APA ·
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APA (6th Edition):
Yracheta, J. M. (2014). A Comparison, Evaluation and Accuracy Assessment of the Fluidigm (TM) Platform in Genotyping Common and Rare variants in an Alaska Native Population. (Thesis). University of Washington. Retrieved from http://hdl.handle.net/1773/25335
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Yracheta, Joseph Manuel. “A Comparison, Evaluation and Accuracy Assessment of the Fluidigm (TM) Platform in Genotyping Common and Rare variants in an Alaska Native Population.” 2014. Thesis, University of Washington. Accessed April 16, 2021.
http://hdl.handle.net/1773/25335.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Yracheta, Joseph Manuel. “A Comparison, Evaluation and Accuracy Assessment of the Fluidigm (TM) Platform in Genotyping Common and Rare variants in an Alaska Native Population.” 2014. Web. 16 Apr 2021.
Vancouver:
Yracheta JM. A Comparison, Evaluation and Accuracy Assessment of the Fluidigm (TM) Platform in Genotyping Common and Rare variants in an Alaska Native Population. [Internet] [Thesis]. University of Washington; 2014. [cited 2021 Apr 16].
Available from: http://hdl.handle.net/1773/25335.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Yracheta JM. A Comparison, Evaluation and Accuracy Assessment of the Fluidigm (TM) Platform in Genotyping Common and Rare variants in an Alaska Native Population. [Thesis]. University of Washington; 2014. Available from: http://hdl.handle.net/1773/25335
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Washington
4.
Jones-Isaac, Kendan Alexander.
The Impact of R10-Hydroxywarfarin on CYP2C9-Mediated S-Warfarin Metabolism.
Degree: 2014, University of Washington
URL: http://hdl.handle.net/1773/25336
► Warfarin therapy is highly effective in treating both atrial fibrillation and deep vein thrombosis. Currently, more than 20 million Americans are receiving warfarin therapy. However,…
(more)
▼ Warfarin therapy is highly effective in treating both atrial fibrillation and deep vein thrombosis. Currently, more than 20 million Americans are receiving warfarin therapy. However, increased risk of adverse events are associated with both under and overdosing the drug. Sub–therapeutic plasma levels may be insufficient to prevent the recurrence of a life–threatening clot. Alternatively, if warfarin levels are too high, the risk of dangerous bleeding events is greatly increased. Inter–individual variability in warfarin sensitivity underlies much of the difficulty in managing treatment by influencing dose requirements in a largely unpredictable manner. For example, one clinical study involving 185 subjects reported a 32–fold difference in daily warfarin doses, from 0.5–16 mg/day, needed to achieve a safe, therapeutic degree of anticoagulation. Many major contributors to this variability have been identified, such as age, race, sex, genetics, as well as several clinical factors. It is estimated that roughly 12% of this variability can be attributed to inherited variants of the Cytochrome P450 2C9 (CYP2C9) isoform. This enzyme is critical for the elimination of the more potent S–enantiomer of warfarin. Another 24–30% can be attributable to different variants of the gene VKORC1 , which codes for the target enzyme that warfarin inhibits. However, about 40% of the variability in the dose required to achieve a therapeutic level of anticoagulation remains unknown. One additional source of variability in warfarin dose–response could arise from mutual pharmacokinetic interactions between R– and S– warfarin enantiomers. An interaction of this kind would be more significant if it primarily impacted S–warfarin clearance, because this enantiomer is 3–5 fold more potent a vitamin K antagonist than R–warfarin. This has been investigated previously. For example, S–warfarin was found to be a weak inhibitor of R–warfarin metabolism, whereas R–warfarin inhibited the production of S–6– and S–7–hydroxywarfarin in human liver microsomes with K
i ranges of 7.0–8.4 μM and 6.0–6.9 μM respectively. In addition, recently, the racemic 4’–, 6–, 7–, 8–, & 10–hydroxyl metabolites of warfarin have been shown to inhibit CYP2C9 mediated hydroxylation of S–warfarin, both in recombinant enzyme incubations and human liver microsomal incubations. In these experiments, the 10–hydroxywarfarin metabolite was reported to be the most potent inhibitor of CYP2C9–dependent activity towards S–warfarin. Because 10–hydroxywarfarin is a major circulating metabolite of warfarin following multiple dosing, we propose that it may reach high enough plasma concentrations at steady–state to produce a significant impact on the disposition and pharmacological response of S–warfarin. To test this hypothesis, we determined the ability of racemic 10–hydroxywarfarin and its four stereoisomers to inhibit S–warfarin 7–hydroxylation using human liver microsomes. We determined the unbound fraction of the 10–hydroxywarfarin stereoisomers in human…
Advisors/Committee Members: Thummel, Kenneth E (advisor).
Subjects/Keywords: 10-Hydroxywarfarin; CYP2C9; Drug; Inhibition; Metabolism; Warfarin; Pharmaceutical sciences; pharmaceutics
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APA ·
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Manager
APA (6th Edition):
Jones-Isaac, K. A. (2014). The Impact of R10-Hydroxywarfarin on CYP2C9-Mediated S-Warfarin Metabolism. (Thesis). University of Washington. Retrieved from http://hdl.handle.net/1773/25336
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Jones-Isaac, Kendan Alexander. “The Impact of R10-Hydroxywarfarin on CYP2C9-Mediated S-Warfarin Metabolism.” 2014. Thesis, University of Washington. Accessed April 16, 2021.
http://hdl.handle.net/1773/25336.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Jones-Isaac, Kendan Alexander. “The Impact of R10-Hydroxywarfarin on CYP2C9-Mediated S-Warfarin Metabolism.” 2014. Web. 16 Apr 2021.
Vancouver:
Jones-Isaac KA. The Impact of R10-Hydroxywarfarin on CYP2C9-Mediated S-Warfarin Metabolism. [Internet] [Thesis]. University of Washington; 2014. [cited 2021 Apr 16].
Available from: http://hdl.handle.net/1773/25336.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Jones-Isaac KA. The Impact of R10-Hydroxywarfarin on CYP2C9-Mediated S-Warfarin Metabolism. [Thesis]. University of Washington; 2014. Available from: http://hdl.handle.net/1773/25336
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Washington
5.
Zheng, Songmao.
The Impact of CYP3A5 Variation and Pregnancy on the Metabolic Disposition of Calcineurin Inhibitors.
Degree: PhD, 2013, University of Washington
URL: http://hdl.handle.net/1773/21733
► The calcineurin inhibitors (CNI) — cyclosporine A (CsA) and tacrolimus remain the backbone of immunosuppression therapy for most organ transplant patients despite their serious side…
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▼ The calcineurin inhibitors (CNI) — cyclosporine A (CsA) and tacrolimus remain the backbone of immunosuppression therapy for most organ transplant patients despite their serious side effects, such as chronic calcineurin inhibitor nephrotoxicity (CNIT). CNIs are substrates for CYP3As and P-glycoprotein. Genetic and environmental factors affect the activity of these proteins and can contribute to inter-individual variability CNI clearance and pharmacological response. In addition, the active concentration of CNIs is affected by physiological changes that influence their binding to plasma and intracellular components. In this dissertation project, the first objective was to investigate the impact of polymorphic CYP3A5 expression on the metabolism of CNIs and to evaluate the hypothesis that CYP3A5 genotype affects intrarenal CNI and metabolite accumulation. The second objective was to characterize the impact of physiological changes induced by pregnancy on tacrolimus disposition and to evaluate in utero and neonatal tacrolimus exposure. For objective one, CsA and tacrolimus were orally administered to 24 healthy participants selected based on their CYP3A5 genotype. Compared to CYP3A5 nonexpressors, expressors had a comparable oral CsA clearance, but 30% higher AUC
metabolite/AUC
CsA ratios for AM19 and AM1c9, and a 20.4% lower mean CsA apparent urinary clearance. For tacrolimus, CYP3A5 expressors had a 1.6-fold higher oral clearance, 2.0- to 2.7-fold higher metabolite/parent AUC ratios for 31-DMT, 12-HT and 13-DMT, and a 36% lower tacrolimus urinary clearance. A semi-physiological model of renal tacrolimus disposition was developed, which predicted that intrarenal tacrolimus exposure in CYP3A5 expressors is 53% of that in nonexpressors. Thus, with chronic therapy, intrarenal accumulation of CNIs and their metabolites will depend on the CYP3A5 genotype of the liver and kidneys, which may contribute to inter-patient differences in the risk of CNIT. The findings for objective two demonstrate that anemia and hypoalbuminemia during pregnancy increase the fraction of unbound tacrolimus. The clinical titration of dosage in pregnancy can lead to elevated unbound concentrations and possibly toxicity. In addition, tacrolimus crosses the placenta, with in utero exposure being approximately 71%, 20% and 20% of maternal exposure when comparing blood, plasma or unbound concentrations, respectively and only small amounts of tacrolimus are excreted into breast milk.
Advisors/Committee Members: Thummel, Kenneth E. (advisor).
Subjects/Keywords: Calcineurin Inhibitors; CYP3A5; intrarenal metabolism; Metabolic Disposition; nephrotoxicity; Pregnancy; Pharmaceutical sciences; Pharmaceutics
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APA ·
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MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Zheng, S. (2013). The Impact of CYP3A5 Variation and Pregnancy on the Metabolic Disposition of Calcineurin Inhibitors. (Doctoral Dissertation). University of Washington. Retrieved from http://hdl.handle.net/1773/21733
Chicago Manual of Style (16th Edition):
Zheng, Songmao. “The Impact of CYP3A5 Variation and Pregnancy on the Metabolic Disposition of Calcineurin Inhibitors.” 2013. Doctoral Dissertation, University of Washington. Accessed April 16, 2021.
http://hdl.handle.net/1773/21733.
MLA Handbook (7th Edition):
Zheng, Songmao. “The Impact of CYP3A5 Variation and Pregnancy on the Metabolic Disposition of Calcineurin Inhibitors.” 2013. Web. 16 Apr 2021.
Vancouver:
Zheng S. The Impact of CYP3A5 Variation and Pregnancy on the Metabolic Disposition of Calcineurin Inhibitors. [Internet] [Doctoral dissertation]. University of Washington; 2013. [cited 2021 Apr 16].
Available from: http://hdl.handle.net/1773/21733.
Council of Science Editors:
Zheng S. The Impact of CYP3A5 Variation and Pregnancy on the Metabolic Disposition of Calcineurin Inhibitors. [Doctoral Dissertation]. University of Washington; 2013. Available from: http://hdl.handle.net/1773/21733
. 
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