Pyelonephritis impacts on Organic Anion Transporters (OAT) 1 and 3 activity in pregnant women: a quantitative system pharmacology approach

• Grant number: 19/03429-4
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: June 01, 2019
• End date: September 30, 2022
• Field of knowledge: Biological Sciences - Pharmacology - Clinical Pharmacology
• Principal Investigator: Vera Lúcia Lanchote
• Grantee: Jhohann Richard de Lima Benzi
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 18/05616-3 - Clinical pharmacokinetics in infectious diseases, AP.TEM
• Associated scholarship(s): 21/10292-5 - Quantitative in vitro to in vivo prediction of the effects of pro-inflammatory cytokines and pregnancy on transporter-mediated drug disposition via PBPK modeling and simulation, BE.EP.DR

Abstract

The investigation of the role of Organic Anion Transporters (OAT) 1 and 3 in the pharmacological therapy as well as factors influencing its activities and/or expression, has been recommended because of its important contribution in the renal excretion of drugs. This project aims to investigate the influence of Pyelonephritis, a bacterial infection with an important inflammatory component in the pharmacokinetics of furosemide (FUR), a probe drug for the activity of OAT 1 and 3. In the first phase of the study, pregnant women (n = 10) with Pyelonephritis with indication for treatment with cefuroxime (CER), will receive endovenous CER (ev) 750 mg/8/8h. After initial CER infusion, the pregnant women will receive a single oral dose of 40 mg FUR. After treatment with CER, the pregnant women will be discharged according to local hospitals protocol and will continue treatment with oral REC 250 mg/8/8h for 10-14 days.In the second phase of the study, pregnant women during oral CER treatment will receive a single oral dose of FUR 40 mg. In addition, the activity of OAT 1 and 3, as well as the Endogenous Biomarkers (EB) taurine and 6²-hydroxycortisol, will be investigated in healthy pregnant women. In the first phase of the study, healthy pregnant women (n = 10) will receive a single oral dose of 40 mg FUR. After wash-out (7 days), pregnant women will receive a single dose of probenecid 750 mg (renal OAT inhibitor) and after 2h, a single oral dose of 40 mg FUR. In both protocols, blood and urine samples will be collected up to 24 hours after FUR administration. Concentrations of FUR and CER and the EB taurine and 6²-hydroxycortisol will be determined in the biological samples by LC-MS/MS. In the second stage of the study, the role of OAT 1 and 3 on cefuroxime and furosemide transport will be elucidated in vitro. The data obtained will be incorporated into PBPK models, in order to predict plasma concentrations of other substrates of OAT 1 and 3 in pregnant women, taking into account the different physicochemical properties of different drugs. (AU)

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)

BENZI, JHOHANN RICHARD DE LIMA; ROCHA, ADRIANA; COLOMBARI, JULIA CRISTINA; PEGO, ALEF MACHADO GOMES; MELLI, PATRICIA PEREIRA DOS SANTOS; DUARTE, GERALDO; LANCHOTE, VERA LUCIA. Determination of furosemide and its glucuronide metabolite in plasma, plasma ultrafiltrate and urine by HPLC-MS/MS with application to secretion and metabolite formation clearances in non-pregnant and pregnant women. Journal of Pharmaceutical and Biomedical Analysis, v. 235, p. 9-pg., 2023-10-25. (21/10292-5, 18/05616-3, 21/00351-4, 19/03429-4)

DE LIMA BENZI, JHOHANN RICHARD; MOREIRA, FERNANDA DE LIMA; MARQUES, MARIA PAULA; DUARTE, GERALDO; SUAREZ-KURTZ, GUILHERME; LANCHOTE, VERA LUCIA. A background subtraction approach for determination of endogenous cortisol and 6 beta-hydroxycortisol in urine by UPLC-MS/MS with application in a within-day variability study in HIV-infected pregnant women. JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES, v. 1144, MAY 1 2020. (19/03429-4, 18/05616-3, 16/23938-2)

Academic Publications

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

BENZI, Jhohann Richard de Lima. Impacts of pregnancy and acute pyelonephritis on in vivo activity of organic anion transporters 1 and 3 employing furosemide pharmacokinetics. 2022. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC) Ribeirão Preto.