Pharmacokinetic screening and in vitro studies for the selection of new thiazolidinediones with promising oral administration capability

• Grant number: 14/20833-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): January 01, 2015
• Effective date (End): September 30, 2016
• Field of knowledge: Health Sciences - Pharmacy
• Acordo de Cooperação: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Rosangela Gonçalves Peccinini
• Grantee: Elias Carvalho Padilha
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Associated scholarship(s): 16/07381-8 - Structural optimization of new compounds for the treatment of fibrodysplasia ossificans progressive based on metabolism profiles acquired through metabolite identification, BE.EP.DR

Abstract

Thiazolidinediones (TZDs) are drugs used to treat type 2 diabetes mellitus (DM2), its mechanism of action occurs by activating PPAR-³ (peroxisome proliferator activated receptors)receptors in the cell nucleus which regulates the expression of genes that affect glucose and lipid metabolism, affects anti-inflammatory activity, decrease blood pressure, cholesterol and triglycerides as well as mitigate the cardiovascular risks of DM2, especially on the progression of atherosclerosis due to the metabolic syndrome that affects these patients. Given the wide application of TZDs and the presence of a single therapeutic alternative in the market, pioglitazone, researchers from the Laboratory of Planning and Synthesis of Drugs at the Federal University of Pernambuco selected several derivatives of TZDs which were promising in relation to anti-atherosclerosis activity. Among the compounds with better performances stood out the GQ-2-(5-(4-chloro-benzylidene)-3-(4-methyl-benzyl)-thiazolidine-2,4-dione), GQ-11 (5-(indol-3-yl-methylene)-3-4-metlbenzil)thiazolidine-2,4-dione), GQ-19 (5-(indol-3-yl-methylene)-3-(4-metlbenzil)-thiazolidine-2,4-dione) and GQ-177. These new drugs intended for the treatment of atherosclerosis it is mandatory to possess noninvasive administration for both patient acceptance (oral administration) and to present competitive advantage over their peers in the market. To determine the oral absorption of these new molecules is possible to employ methods of pharmacokinetic screening, among the screenings methods there is the CARRS which is one that uses fewer animals and no risk of interactions between substances, described by Korfmacher and employees of the Research Institute of Schering-Plough (2001). This method requires only 2 animals per drug, taken orally, and 6 sampling times over 6 hours. Besides the pharmacokinetic screening, physicochemical characteristics are easily assessed and generate relevant information to the absorption process, the determination of LogP, for example, has a direct influence on the events that follow the enteral administration of drugs, because it relates directly with the solubility of the compound in the stomach and intestinal fluids, and also influences the permeability of the drug through cell membranes involved in the process of absorption. Also, in vitro tests, such as the Caco-2 monolayers model also contribute to determine and understand the oral absorption of drugs. These cells mimic the intestinal wall and its relevance to the development of drugs is recognized by the key regulatory agencies which indicate this test for predicting oral absorption of drugs Thus, this project aims to use the pharmacokinetic screening by CARRS, the model monolayers of Caco-2 cells and the determination of physicochemical characteristics to select from among the compounds derived from thiazolidinediones - GQ-2, GQ-11, GQ-19 and GQ-177 - the candidate(s) with characteristics better suited to the continuity of pre-clinical studies. (AU)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

PADILHA, Elias Carvalho. Pharmacokinetic screening and in vitro studies for the selection of new thiazolidinediones with promising oral administration capability. 2017. Doctoral Thesis - Universidade Estadual Paulista (Unesp). Faculdade de Ciências Farmacêuticas. Araraquara Araraquara.