Advanced search options

Advanced Search Options 🞨

Browse by author name (“Author name starts with…”).

Find ETDs with:

in
/  
in
/  
in
/  
in

Written in Published in Earliest date Latest date

Sorted by

Results per page:

Sorted by: relevance · author · university · dateNew search

You searched for subject:(Phase II metabolites). Showing records 1 – 2 of 2 total matches.

Search Limiters

Last 2 Years | English Only

No search limiters apply to these results.

▼ Search Limiters


Universidade Nova

1. Fidalgo, Lara Gião. Sulfonate and acetyl derivatives of the vasopressin antagonist tolvaptan: reactivity towards DNA and 2’-deoxynucleosides.

Degree: 2016, Universidade Nova

Tolvaptan is an orally effective nonpeptide arginine vasopressin (AVP) V2-receptor antagonist, used in the treatment of clinically significant euvolemic and hypervolemic hyponatremia. Nonetheless, Tolvaptan was reported to be associated with a high risk of liver injury, prompting the U. S. Food and Drug Administration (FDA) to issue a black box label warning. Whereas the mechanisms of tolvaptan-induced liver injury remain to be elucidated, preliminary results obtained in cytochrome P450 (CYP)-deficient liver cell lines have shown evidence of tolvaptaninduced DNA damage without the need for Phase I metabolism. Taking into consideration that Phase II sulfonation and/or acetylation of tolvaptan’s secondary alcohol are metabolically plausible events, the ultimate goal of this thesis was to study the reactivity of these putative Phase II metabolites towards DNA. Indeed, the covalent adducts thus afforded could explain the tolvaptan-induced DNA damage observed in CYP-deficient liver cell lines. Since the identification of DNA adducts involves the hydrolysis to 2’-deoxynucleobase adducts followed by liquid chromatography coupled with mass spectrometry (LC-ESI-MS) in comparison with adducts standards, the first step of this thesis was the preparation of tolvaptan-DNA adduct standards. Two distinct strategies were followed: 1) biomimetic, involving the reaction of the metabolic plausible sulfate and acetate tolvaptan metabolites with 2’-deoxynucleobases; 2) non-biomimetic, involving a palladium-catalyzed coupling reaction. For the biomimetic approach, the two metabolic plausible Phase II metabolites were first prepared: 1) 5’-O-sulfonate-tolvaptan was prepared in 89 % yield upon tolvaptan sulfonation using sulfur trioxide-pyridine complex; 2) 5’-O-acetyl-tolvaptan was prepared in 80% following tolvaptan acetylation with acetic anhydride and trimethylamine. The reaction of 5’-O-sulfonate-tolvaptan and 5’-O-acetyl-tolvaptan with 2’-deoxynucleobases (and nucleophilic amino acids) were subsequently undergone, with the ultimate goal of preparing adduct standards. However, only the product stemming from the elimination of sulfoxy and acetoxy groups was detected, upon LC-ESI-MS analysis of these reaction mixtures. For the non-biomimetic strategy, the derivative 5’-chloro-tolvaptan was prepared upon reaction of tolvaptan with thionyl chloride, and subsequently coupled with 3′,5′-O-bis(tertbutyldimethylsilyl)-2′-deoxyguanosine, under palladium catalysis. Following deprotection, the LC-ESI-HRMS analysis of the reaction mixture allowed the identification of two covalent adducts, one non-depurinating and one depurinating. The reaction of 5’-O-sulfonate-tolvaptan and 5’-O-acetyl-tolvaptan with DNA were also undergone. However, the LC-ESI-HRMS analysis of the hydrolysates obtained following enzymatic or thermic hydrolysis did not allow the identification of any tolvaptan-DNA adduct. This result suggests that the DNA damage observed in hepatic cell lines does not stem from the formation of DNA adducts with the metabolic plausible Phase II… Advisors/Committee Members: Antunes, Alexandra, Branco, Paula.

Subjects/Keywords: Tolvaptan; Phase II metabolites; DNA adducts; 2’-deoxynucleobases; 5’-O-acetyl- tolvaptan; 5’-O-sulfonate-tolvaptan; Domínio/Área Científica::Engenharia e Tecnologia::Engenharia Química

Record DetailsSimilar RecordsGoogle PlusoneFacebookTwitterCiteULikeMendeleyreddit

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Fidalgo, L. G. (2016). Sulfonate and acetyl derivatives of the vasopressin antagonist tolvaptan: reactivity towards DNA and 2’-deoxynucleosides. (Thesis). Universidade Nova. Retrieved from http://www.rcaap.pt/detail.jsp?id=oai:run.unl.pt:10362/18454

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):

Fidalgo, Lara Gião. “Sulfonate and acetyl derivatives of the vasopressin antagonist tolvaptan: reactivity towards DNA and 2’-deoxynucleosides.” 2016. Thesis, Universidade Nova. Accessed November 16, 2019. http://www.rcaap.pt/detail.jsp?id=oai:run.unl.pt:10362/18454.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Fidalgo, Lara Gião. “Sulfonate and acetyl derivatives of the vasopressin antagonist tolvaptan: reactivity towards DNA and 2’-deoxynucleosides.” 2016. Web. 16 Nov 2019.

Vancouver:

Fidalgo LG. Sulfonate and acetyl derivatives of the vasopressin antagonist tolvaptan: reactivity towards DNA and 2’-deoxynucleosides. [Internet] [Thesis]. Universidade Nova; 2016. [cited 2019 Nov 16]. Available from: http://www.rcaap.pt/detail.jsp?id=oai:run.unl.pt:10362/18454.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Fidalgo LG. Sulfonate and acetyl derivatives of the vasopressin antagonist tolvaptan: reactivity towards DNA and 2’-deoxynucleosides. [Thesis]. Universidade Nova; 2016. Available from: http://www.rcaap.pt/detail.jsp?id=oai:run.unl.pt:10362/18454

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

2. Gómez Castellà, Cristina, 1985-. Improving detection capabilities of doping agents by identification of new phase I and phase II metabolites by LC-MS/MS.

Degree: Departament de Ciències Experimentals i de la Salut, 2014, Universitat Pompeu Fabra

Els estudis metabòlics de substàncies dopants han estat tradicionalment realitzats mitjançant l’ús de cromatografia de gasos acoblada a espectrometria de masses (GC-MS). En els últims anys, s’ha demostrat la utilitat de la cromatografia líquida acoblada a espectrometria de masses (LC-MS) per realitzar estudis de metabolisme. L’objectiu d’aquesta tesi va ser estudiar el metabolisme (fase I i fase II) de diferents substàncies dopants mitjançant LC-MS/MS per tal de millorar la capacitat de detecció dels compostos estudiats. Per a mesocarb, compost termolàbil, es van detectar en orina el compost inalterat i 19 metabòlits incloent metabòlits mono-, di- i tri-hidroxilats excretats lliures o conjugats amb àcid glucurònic i sulfat. Per a toremifè, un fàrmac anti-estrogènic amb espectre de masses d’impacte electrònic amb pocs ions diganòstic, es van detectar el compost inalterat i 20 metabòlits en orina. Es va proposar l’estructura de la major part de metabòlits detectats. Per tal de millorar la retrospectivitat de la detecció dels esteroides anabolitzants androgènics (AAS) es van estudiar els metabòlits conjugats amb sulfat. Es va realitzar un estudi de la hidròlisi i del comportament espectromètric dels metabòlits conjugats amb sulfat dels AAS. Es van estudiar els metabòlits conjugats amb sulfat de boldenona, metiltestosterona i metandienona. Es van identificar boldenona sulfat i epiboldenona sulfat com a metabòlits de boldenona en humans. Aquests metabòlits poden ser usats com a marcadors de l’administració exògena de boldenona. Per a metiltestosterona, es van detectar i proposar les estructures de tres nous metabòlits conjugats amb sulfat. Un d’ells, el 17β-metil-5α-androstà-3α,17α-diol 3α-sulfat, va ser detectat en orina fins a 21 dies després de l’administració de metiltestosterona. Es van detectar diversos metabòlits de metandienona conjugats amb sulfat no descrits prèviament. Un d’ells, identificat com a 18-nor-17β-hidroximetil-17α-metilandrost-1,4,13-trien-3-ona conjugat amb sulfat, va ser detectat fins 26 dies després de l’administració. Tant per a metiltestosterone com per a metandienone, els metabòlits conjugats amb sulfat permeten millorar la retrospectivitat de la detecció respecte a altres marcadors descrits anteriorment. S’ha demostrat la utilitat del LC-MS/MS per a la detecció i caracterització de metabòlits de substàncies dopants, especialment per a l’estudi de nous metabòlits de fase II i per a estudis de metabolisme de compostos que mostren limitacions en GC-MS. Advisors/Committee Members: [email protected] (authoremail), true (authoremailshow), Ventura Alemany, Rosa (director), true (authorsendemail).

Subjects/Keywords: Liquid chromatography tandem mass spectrometry; Metabolism; Doping agents; Doping analysis; Phase I and phase II metabolites; Sulphate metabolites; Cromatografia líquida-espectrometria de masses; Metabolisme; Substàncies dopants; Dopatge; Metabòlits de fase I i fase II; Metabòlits conjugats amb sulfat; 615

…demonstrated, especially for the study of new phase II metabolites and for metabolic studies of… …xiii Preface and the impossibility to directly analyse phase II metabolites (… …possibility to directly analyse phase II metabolites and to the directly detect polar compounds… …deconjugate the phase II metabolites. 7 Chapter 1 The presence in a sample of a prohibited… …Detection and characterization of metabolites of boldione by LC-MS/MS. Part I: Phase I metabolites… 

Record DetailsSimilar RecordsGoogle PlusoneFacebookTwitterCiteULikeMendeleyreddit

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Gómez Castellà, Cristina, 1. (2014). Improving detection capabilities of doping agents by identification of new phase I and phase II metabolites by LC-MS/MS. (Thesis). Universitat Pompeu Fabra. Retrieved from http://hdl.handle.net/10803/132539

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):

Gómez Castellà, Cristina, 1985-. “Improving detection capabilities of doping agents by identification of new phase I and phase II metabolites by LC-MS/MS.” 2014. Thesis, Universitat Pompeu Fabra. Accessed November 16, 2019. http://hdl.handle.net/10803/132539.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Gómez Castellà, Cristina, 1985-. “Improving detection capabilities of doping agents by identification of new phase I and phase II metabolites by LC-MS/MS.” 2014. Web. 16 Nov 2019.

Vancouver:

Gómez Castellà, Cristina 1. Improving detection capabilities of doping agents by identification of new phase I and phase II metabolites by LC-MS/MS. [Internet] [Thesis]. Universitat Pompeu Fabra; 2014. [cited 2019 Nov 16]. Available from: http://hdl.handle.net/10803/132539.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Gómez Castellà, Cristina 1. Improving detection capabilities of doping agents by identification of new phase I and phase II metabolites by LC-MS/MS. [Thesis]. Universitat Pompeu Fabra; 2014. Available from: http://hdl.handle.net/10803/132539

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

.