| Grant number: | 16/04927-0 |
| Support Opportunities: | Regular Research Grants |
| Start date: | October 01, 2016 |
| End date: | September 30, 2018 |
| Field of knowledge: | Biological Sciences - Pharmacology - Toxicology |
| Principal Investigator: | Rosangela Gonçalves Peccinini |
| Grantee: | Rosangela Gonçalves Peccinini |
| Host Institution: | Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil |
| Associated researchers: | Michel Leandro de Campos |
Abstract
Poor pharmacokinetic properties and toxicity constitute more than 50% of important causes of costly late-stage failures in drug development to produce alternative therapies for humans. Thus, the pharmacokinetics should be evaluated earlier in the drug development, for the simultaneous improvement of the pharmacokinetics and pharmacological potency that may result in a more promising candidate for therapeutic use. The knowledge of features such asdrug permeation capacity and susceptibility to metabolism provides proper planning of the first pharmacokinetic studies in animal models and may direct the selection of these models, the appropriate route of administration as well as aiding interpretation of results obtained fromin vivo studies. The model Caco-2 cell monolayers mimic several aspects of intestinal wall and their relevance for the development of drugs is recognized by regulatory agencies, which indicate it as a predictive test for oral drug absorption. The in vitro metabolism assay may be performed with cells or cellular fractions of the animal model in which one plans to conduct the pharmacokinetics test. The use of human cells or cellular fractions allows the correlation of the clearances observed in vitro and in vivo and the calculus of the predicted human clearance. This project aims to implement the model of monolayers of Caco-2 cells and in vitro metabolism studies at the Laboratory of the Research Group of FCFAr / UNESP to obtain relevant information to the reasoning of the planning of pre-clinical trials in order to accelerate assessments of pharmacokinetic profile of the new molecule drug candidates and select from the following the (s) candidate (s) with the most appropriate characteristics for the continuity of preclinical studies. To implement the Caco-2 monolayer model the phthalimide derivatives LAPDESF-SCD03 and LAPDESF-SCD04 were selected, and for the implementation of in vitrometabolism assays the molecules GQ-11, GQ-19 and GQ-177 were selected. After implementation, the aforementioned assays will be part of the preliminary tests in the preclinical drug development of all drug candidates studied by the research group of FCFAr / UNESP. (AU)
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