Abstract
PurposeTo provide whole-body physiologically based pharmacokinetic (PBPK) models of the potent clinical organic anion transporter (OAT) inhibitor probenecid and the clinical OAT victim drug furosemide for their application in transporter-based drug-drug interaction (DDI) modeling.MethodsPBPK models of probenecid and furosemide were developed in PK-Sim®. Drug-dependent parameters and plasma concentration-time profiles following intravenous and oral probenecid and furosemide administration were gathered from literature and used for model development. For model evaluation, plasma concentration-time profiles, areas under the plasma concentration–time curve (AUC) and peak plasma concentrations (Cmax) were predicted and compared to observed data. In addition, the models were applied to predict the outcome of clinical DDI studies.ResultsThe developed models accurately describe the reported plasma concentrations of 27 clinical probenecid studies and of 42 studies using furosemide. Furthermore, application of these models to predict the probenecid-furosemide and probenecid-rifampicin DDIs demonstrates their good performance, with 6/7 of the predicted DDI AUC ratios and 4/5 of the predicted DDI Cmax ratios within 1.25-fold of the observed values, and all predicted DDI AUC and Cmax ratios within 2.0-fold.ConclusionsWhole-body PBPK models of probenecid and furosemide were built and evaluated, providing useful tools to support the investigation of transporter mediated DDIs.
Highlights
Many important drug transporters are members of the solute carrier (SLC) family, which is widely expressed throughout the human body and mediates influx or efflux of endogenous and exogenous substrates [1]
Organic anion transporter (OAT) 1 and OAT3 are members of the SLC transporter family (SLC22A6, SLC22A8) and recognized as important drug transporters from the perspective of their potential to be involved in clinically relevant drug-drug interaction (DDI)
OAT1 and OAT3 are predominantly expressed in the kidney at the basolateral membrane of proximal tubule cells [4], where they facilitate the uptake of endogenous and exogenous organic anions from the blood into the proximal tubule cells [5], from where they can be secreted into the nephron lumen for excretion with the urine
Summary
Many important drug transporters are members of the solute carrier (SLC) family, which is widely expressed throughout the human body and mediates influx or efflux of endogenous and exogenous substrates [1]. For the approval of new drugs, the U.S Food and Drug Administration (FDA) and the European Medicines Agency (EMA) require various in vitro, and in many cases, clinical studies to characterize the transporter mediated drug-drug interaction (DDI) potential of investigational drugs. Organic anion transporter (OAT) 1 and OAT3 are members of the SLC transporter family (SLC22A6, SLC22A8) and recognized as important drug transporters from the perspective of their potential to be involved in clinically relevant DDIs. OAT1 and OAT3 are predominantly expressed in the kidney at the basolateral membrane of proximal tubule cells [4], where they facilitate the uptake of endogenous (e.g. paminohippurate, estrone sulfate) and exogenous (e.g. diuretic drugs) organic anions from the blood into the proximal tubule cells [5], from where they can be secreted into the nephron lumen for excretion with the urine. Probenecid can be used to investigate organic anion transporting polypeptide (OATP) 1B1 mediated DDIs [9]
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