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IMPLEMENTING OF IN VITRO PERMEATION AND METABOLISM TESTING OF DRUG CANDIDATES

Grant number: 16/04927-0
Support Opportunities:Regular Research Grants
Duration: October 01, 2016 - 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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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CAMPOS, MICHEL LEANDRO; CERQUEIRA, LETICIA BONANCIO; ULIAN SILVA, BRUNA CRISTINA; FRANCHIN, TAISA BUSARANHO; GALDINO-PITTA, MARINA ROCHA; PITTA, IVAN ROCHA; PECCININI, ROSANGELA GONCALVES; PONTAROLO, ROBERTO. New Pioglitazone Metabolites and Absence of Opened-Ring Metabolites in New N-Substituted Thiazolidinedione. DRUG METABOLISM AND DISPOSITION, v. 46, n. 6, p. 879-887, . (16/04927-0)

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