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Elucidation of the metabolism of nitrosyl ruthenium complex as a new class of metallo-drugs: in vitro and in vivo and in aqueous solution and in system of drug delivery studies

Grant number: 11/13470-0
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): November 01, 2011
Effective date (End): October 31, 2012
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Roberto Santana da Silva
Grantee:Fabiana de Souza Oliveira
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:09/51812-0 - Development of a platform for the study of in vitro and in vivo metabolism of natural products, a need for pre-clinical testing system, AP.BTA.TEM

Abstract

Nitric oxide (NO) is a radical species involved in many biological processes. Despite the great importance of NO in biological systems, studies of their pharmacological properties are limited due to its high reactivity and short half-life. Thus, the development of compounds that can release NO, could be an alternative to solve these problems and be potentially used as therapeutic agents. The compound sodium nitroprusside (SNP) is a classic NO donor and is used in clinical settings, especially in the treatment of angina. Due to the chemical structure of the NPS, NO release is accompanied by the release of CN-ions, which can be toxic to the body. Due to these toxic effects of NPS, some metalonitrosilos complexes have been studied as promising donors of NO. Among these stands out the ruthenium complexes coordinated nitrosyl ligand - {Ru-NO}+. These compounds have been developed by the research group of Prof. Dr. Roberto Santana da Silva (FCFRP / USP) and shows vasodilatation activity similar to NPS, but without the toxic effect that involves the release of cyanide ions, and cytotoxic effect against certain cancer cell lines, given the synergistic effect of the fragment metal complex NO. Although these compounds have shown promise as a class of metallo-drugs, in vitro and in vivo will be needed to better evaluate its properties, before the development of a new drug. In vitro metabolism studies represent the first step in determining the possible metabolites formed during the administration of this compound. Thus, this project aims, conduct a study of metabolism of complexes of type [Ru(N)4LNO]n+ using the fraction of microsomes isolated from livers of rats, to characterize the possible CYP450 enzymes involved and the effect of the compound on these enzymes using isoenzymes isolated DNA clone and characterize the possible metabolites formed by liquid chromatography coupled to mass spectrometry. Finally, we intend to also perform a preliminary study of kinetic disposition in rats. The development of this project is directly related to research grants approved (Roberto Santana da Silva 2010/11937-5 and Norberto Peporine Lopes 2009/51812-0) and ongoing