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Impact of Roux-en-Y gastric bypass bariatric surgery on system pharmacology: single-dose cross-over pharmacokinetic study of simvastatin and carvedilol

Grant number: 18/06569-9
Support type:Regular Research Grants
Duration: February 01, 2019 - January 31, 2021
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Natália Valadares de Moraes
Grantee:Natália Valadares de Moraes
Home Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
Assoc. researchers: Ajith Kumar Sankarankutty ; Cristiane Masetto de Gaitani ; José Sebastião dos Santos ; Wilson Salgado Junior


The impact of anatomical changes of the gastrointestinal tract resulting from bariatric surgery on pharmacokinetics are due to changes in gastric and intestinal pH, reduction in intestinal transit time, changes in the surface area available for absorption and changes in the abundance of enzymes and drug carriers. Physiologycally based pharmacokinetic (PBPK) models have been developed to predict the effect of bariatric surgery on pharmacokinetics. PBPK models are promising for individualized pharmacological therapy, since they may predict pharmacokinetic parameters for drugs clinically available or for new drug candidates. However, limitations of the model are related to the few clinical studies performed in this population with appropriate design. This study proposes to perform two cross-over studies to investigate the kinetic disposition of simvastatin (Study A) and carvedilol in 3 steps: before, 4-6 months after surgery, and 10-12 months after Roux-en Y gastric bypass bariatric surgery (RYGB). The expression of CYP3A4 and P-glycoprotein (mRNA) will be evaluated in intestinal biopsies collected during preoperative endoscopy, during RYGB and post-surgery. The data from these studies will be used to built mechanistic models to predict the kinetic disposition in complex patients, since bariatric RYGB surgery can significantly alter Systems Pharmacology. (AU)