Impact of pyelonephritis on the activity of organic anion transporters (OAT) 1 and 3 in pregnant women: a quantitative approach to systems pharmacology

Abstract

Infections associated with high plasma concentrations of pro-inflammatory cytokines alter the expression/activity of drug transporters, among which, the organic anion transporters (OATs) 1 and 3 are of fundamental importance in the excretion and consequently in the medication dosing regimen. However, little is knows about the influence of inflammation associated with a kidney infection, especially in pregnant women, in the expression/activity of these transporters. The present study aims to evaluate the influence of pyelonephritis on the activity of OATs 1 and 3 in vitro, in silico and clinical studies during the second and third trimesters of pregnancy, using furosemide as a drug marker and taurine and 6²-hydroxycortisol as endogenous biomarkers. The study employs Quantitative Systems Pharmacology (QSP) in theoptimization of pharmacological therapy using pharmacokinetics as tools (popPK) with data from the clinical study as well as pharmacokinetics-based physiology (PBPK - Physiologically Based Pharmacokinetic) with data from in vitro, clinical and silica studies. Healthy pregnant women (n = 10) and pregnant women with pyelonephritis (n = 10), in the second and third trimesters of pregnancy, as well as healthy non-pregnant volunteers (n = 11). Pregnant women diagnosed with pyelonephritis will be treated with intravenous antibiotics (PHASE I), according to the clinical protocol of the local hospital, during hospital stay, followed by oral antibiotics for 10-14 days after discharge hospital (PHASE II). Pregnant women with pyelonephritis will receive a single oral dose of the drug furosemide marker (FUR) 40 mg in PHASES I and II of the study, while pregnant women patients will receive a single oral dose of FUR 40 mg as monotherapy and in combination with single oral probenecid 750 mg (renal OAT inhibitor). Healthy volunteers will receive a single oral dose of FUR 40 mg. Serial samples of blood and urine will be collected within 24 hours after FUR administration. Plasma/urinary concentrations of FUR and CER, endogenous biomarkers taurine and 6²-hydroxycortisol and cytokines INF, TNF, IL-6, IL-8, C-reactive protein will be determined by LC-MS/MS or immunoassays. The in vitro studies in HEK293 cells will be conducted to elucidate the participation of OATs 1 and 3 in the transport of CER and FUR. In vitro and clinical data will be incorporated in silica toPBPK models, with the objective of predicting the plasma concentrations of other substrates of OATs 1 and 3 in pregnant women. (AU)