Look-up in Google Scholar
Title: Pharmacometrics and Metabolonomics of Selected Chiral Flavonoids
Other Titles: Farmacometría y metabolonómica de flavonoides quirales seleccionados
Advisor(s): Davies, Neal M.
OCDE field: https://purl.org/pe-repo/ocde/ford#3.01.05
Issue Date: May-2008
Institution: Washington State University
Abstract: Se desarrollaron y validaron por primera vez métodos de HPLC simples, estereoselectivos, precisos, reproducibles e isocráticos para la cuantificación de enantiómeros de hesperetina, naringenina y eriodictiol. Se estudiaron los parámetros farmacocinéticos estereoespecíficos tras la administración intravenosa de hesperetina, naringenina y eriodictiol en ratas, se caracterizaron y modelaron utilizando el software farmacocinético WinNonlin®. Cada flavanona se sometió a una glucuronidación extensa y se eliminó predominantemente por vías no renales. Se observaron diferencias en los parámetros farmacocinéticos entre los enantiómeros. Las tres flavanonas estaban muy distribuidas en los tejidos y el hígado las extraía moderadamente. Las vidas medias séricas de estos compuestos parecen ser relativamente cortas. El contenido estereoespecífico en jugos de frutas cítricas mostró un predominio de la forma de glucósido y el enantiómero S(-) y el epímero (2S). La actividad farmacodinámica de hesperetina, hesperidina, naringenina y naringina se determinó en un modelo experimental de colitis ulcerosa utilizando un nuevo método de detección de excreción de rojo fenol. La administración oral de estas flavanonas seleccionadas redujo el daño colónico en este modelo experimental. Los resultados son paralelos a la actividad in vitro, lo que indica que estos compuestos son productos naturales bioactivos que deben someterse a un mayor escrutinio experimental.

Flavonoids are naturally occurring compounds found in a wide range of plant sources. They exhibit potent anti-cancer, anti-inflammatory, and anti-oxidant activities. Flavanones are a sub-class of flavonoids that present a unique structural characteristic of chirality. The scope of this thesis is centered on these three selected flavanones: hesperetin, naringenin, and eriodictyol. These compounds have been well characterized as achiral entities overlooking their enantiospecific pharmacokinetics and pharmacodynamics. Simple, stereoselective, accurate, reproducible and isocratic high-performance liquid chromatography (HPLC) methods were developed and validated for the first time for the quantification of hesperetin, naringenin, and eriodictyol enantiomers. These novel methods were applied to assess the pharmacokinetic parameters of these compounds and their content in various fruit juices. The stereospecific pharmacokinetic parameters following intravenous administration of hesperetin, naringenin, and eriodictyol in male Sprague Dawley rats were characterized and modeled using WinNonlin® pharmacokinetic software. Each flavanone underwent extensive glucuronidation and was predominantly eliminated via non-renal routes. Differences in pharmacokinetic parameters were observed between enantiomers. All three flavanones were highly distributes into tissues and were moderately extracted by the liver. The detectable serum half-lives of these compounds appears to be relatively short. However, utilizing urinary concentration-time data, much longer elimination half-lives were revealed. The stereospecific content of these compounds in citrus fruit juices exhibited a predominance of the glycoside form and the S(-)-enantiomer and (2S)-epimer of the studied flavanones. Hesperetin, naringenin, eriodictyol and their corresponding glycosides: hesperidin, naringin, and eriodictyol were tested in several in vitro models. It was observed that these compounds exhibit concentration-dependant anti-inflammatory properties, cyclooxygenase-1 and -2 (COX-1 and -2) inhibitory activity, anti-cancer activity, anti-oxidant capacity, anti-adipogenic activity, and inflammatory bowel disease activity. The aglycones were more active than the glycosides, and the activity varied from one another and was dependent on differences in methoxy, and hydroxyl moiety substitutions and glycosylation patterns. Individual enantiomers exhibited activity in an anti-cancer study although this activity was not always additive. The pharmacodynamic activity of hesperetin, hesperidin, naringenin, and naringin was determined in an experimental model of ulcerative colitis using a novel detection method of phenol red excretion. The oral administration of these selected flavanones reduced the colonic damage in this experimental model. The results parallel the in vitro activity indicating that these compounds are bioactive natural products that should undergo further experimental scrutiny.
Discipline: Farmacología y Toxicología
Grade or title grantor: Washington State University. Department of Pharmaceutical Sciences
Grade or title: Doctor en Filosofía - Farmacología y Toxicología
Juror: Elstad, Catherine; Hatefi, Arash; Andrews, Preston
Register date: 19-Jul-2022

Files in This Item:
File Description SizeFormat 
YanezFarfanJA.pdfTesis4.55 MBAdobe PDFThumbnail
View/Open
Autorizacion.pdf
  Restricted Access
Autorización del registro198.06 kBAdobe PDFView/Open Request a copy


This item is licensed under a Creative Commons License Creative Commons