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dc.contributor.advisorThummel, Kenneth E.en_US
dc.contributor.authorZheng, Songmaoen_US
dc.date.accessioned2013-02-25T17:48:44Z
dc.date.available2015-12-14T17:55:47Z
dc.date.issued2013-02-25
dc.date.submitted2012en_US
dc.identifier.otherZheng_washington_0250E_10860.pdfen_US
dc.identifier.urihttp://hdl.handle.net/1773/21733
dc.descriptionThesis (Ph.D.)--University of Washington, 2012en_US
dc.description.abstractThe 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 <italic>CYP3A5</italic> expression on the metabolism of CNIs and to evaluate the hypothesis that <italic>CYP3A5</italic> 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 <italic>CYP3A5</italic> genotype. Compared to CYP3A5 nonexpressors, expressors had a comparable oral CsA clearance, but 30% higher AUC<sub>metabolite</sub>/AUC<sub>CsA</sub> 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 <italic>CYP3A5</italic> 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.en_US
dc.format.mimetypeapplication/pdfen_US
dc.language.isoen_USen_US
dc.rightsCopyright is held by the individual authors.en_US
dc.subjectCalcineurin Inhibitors; CYP3A5; intrarenal metabolism; Metabolic Disposition; nephrotoxicity; Pregnancyen_US
dc.subject.otherPharmaceutical sciencesen_US
dc.subject.otherPharmaceuticsen_US
dc.titleThe Impact of CYP3A5 Variation and Pregnancy on the Metabolic Disposition of Calcineurin Inhibitorsen_US
dc.typeThesisen_US
dc.embargo.termsDelay release for 2 years -- then make Open Accessen_US


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