Influence of pyelonephritis in pregnant women on the activity of membrane transporters OATP1B1 and OCT2

• Grant number: 23/04443-6
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: August 01, 2023
• End date: December 31, 2025
• Field of knowledge: Health Sciences - Medicine - Maternal and Child Health
• Principal Investigator: Geraldo Duarte
• Grantee: Ana Cláudia Rabelo e Silva
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 18/05616-3 - Clinical pharmacokinetics in infectious diseases, AP.TEM

Abstract

This research aims to elucidate how pyelonephritis (the most serious urinary tract infection in pregnancy, with an evident inflammatory component) modulates the activity of membrane transporters in pregnant women, providing a better fundation in the fute for safer use of drugs in this special population, also to help predict fetal drug exposure. Objective: To evaluate the influence of pyelonephritis on the activity of OATP1B1 and OCT2 transporters during the second and third trimesters of pregnancy (using rosuvastatin and metformin as marker drugs). Methods: This is an observational, longitudinal and prospective study. We will evaluate 13 pregnant women diagnosed with pyelonephritis who are in the second or third trimester of pregnancy, with indication for treatment with intravenous antibiotics. The clinical protocol will take place at University Hospital of the Ribeirão Preto Medical School (HC-FMRPUSP) and will be divided into: a) Phase I, carried out at the Obstetrics Division of HC-FMRPUSP, where blood samples will be collected for biochemical and hematological tests, also for the analysis of inflammatory cytokines and genotype. Afterwards, a single oral dose of the marker drugs will be administered: rosuvastatin (5 mg) and metformin (500 mg), then we will perform serial blood collections for 24 h, which will be frozen and stored until pharmacokinetic analysis; b) Phase II, performed at the Clinical Research Unit (UPC), when were convenient for the participant after finishing the subsequent treatment with oral antibiotics, where all the same procedures described in Phase I will be performed (except genotype analysis). The analyzes will be carried out at the Laboratory of Clinical Pharmacokinetics (PKCLIN) of the Faculty of Pharmaceutical Sciences of Ribeirão Preto (FCFRP-USP), using ultra-efficiency liquid chromatography with detection by mass spectrometry (UPLC-MS/MS), through some protocols already validated and others that will be developed. Pharmacokinetic parameters (as AUC and total clearance) will be calculated based on plasma concentrations obtained experimentally using the Phoenix WinNonlin software. Project data will be stored and managed using Research Electronic Data Capture (REDCap). Statistical analyzes will be carried out using the R software. The kinetic disposition of the marker drugs will be evaluated between phases (before and after treatment) using Student's t test or Wilcoxon's non-parametric test. The relations between rosuvastatin renal clearance and CP-I and CP-III biomarkers will be evaluated by Pearson's coefficient; all with a significance level set at 5%. The project will be funded by the São Paulo Research Foundation (FAPESP), through the FAPESP Thematic Process: 2018/05616-3. (AU)