In patients with renal impairment, tubular secretion of drugs via drug transporters is reduced. As a possible mechanism, the chronic inflammatory state associated with renal injury may affect the expression and activity of drug transporters. However, the relationship between inflammatory status and drug transporter expression have not been clarified using patient samples. In this study, we analyzed the expression levels of drug transporters in human kidney specimens and examined the effects of inflammatory cytokines on the expression and activity of renal drug transporters, organic anion transporter (OAT) 1 and 3, using three-dimensionally cultured human proximal tubular epithelial cells (3D-RPTEC) [1,2]. Proteomic analysis of non-tumor portion specimens of kidneys removed from patients with renal tumors revealed 93 transporters including OAT1. Enrichment analysis of proteins negatively correlated with OAT1 and OAT3 expression in human kidney using Metascape revealed GO terms related to inflammation. To characterize the direct effects of inflammatory cytokines on RPTECs, IL-1β and TNFα were exposed to 3D-RPTECs. As a result, mRNA expression of OAT1 and OAT3 was decreased and the uptake activity of the OAT1 substrate [3H] PAH was reduced. The decrease in mRNA expression due to inflammatory cytokine exposure was suppressed by the addition of the NF-κB inhibitor benzoxathiole. In conclusion, our studies revealed that inflammatory cytokines negatively regulate the expression of renal drug transporters OAT1 and OAT3.

This webinar is intended to enable ADME and DMPK scientists to understand how emerging machine learning and high-throughput PBPK approaches can enable earlier, more scalable prediction of pharmacokinetics and support decision-making for complex drug candidates.

ATP binding cassette (ABC) and solute carrier (SLC) placental transport proteins (i.e., transporters) regulate the transfer of nutrients, endogenous compounds, drugs and metabolites between mother and fetus, impacting fetal development and pregnancy outcomes. Identification and accurate quantification of these transporters is critical for predicting nutrient and drug disposition and assessing drug safety throughout pregnancy. Proteomic approaches—both targeted and untargeted—offer complementary strategies for identifying and quantifying transporter abundance in placental tissue of varying gestational age. This webinar will feature work conducted at the University of Washington Transporter Elucidation Center (UWTEC) and the Integrated Transporter Elucidation Center (InTEC) to elucidate which transporters are present in the placenta at different gestational ages and at what levels. The aims of the presentation are to emphasize the pharmacological importance of accurately identifying and quantifying placental transporters at different gestational ages, to predict human fetal drug and nutrient exposure using physiologically based pharmacokinetic (PBPK) modeling, to illustrate how experimental methodology influences data variability, and to highlight novel associations between maternal and infant factors, including environmental chemical exposures, and ABC and SLC transporter enrichment in the placenta.

This award recognizes an ISSX member who has made groundbreaking and continued scientific accomplishments in the field of Drug Discovery and Development. It represents the peak of scientific recognition within ISSX and celebrates vision, dedication, and achievement.

Named in honor of R.T. Williams, this award recognizes an ISSX member who has made seminal and sustained scientific contributions to the field. It represents the pinnacle of scientific recognition within ISSX and celebrates vision, dedication, and achievement at the highest international level.

This webinar is designed to provide an updated understanding of intestinal secretion, biliary elimination, and their roles in drug clearance, while addressing existing knowledge gaps in predicting direct intestinal excretion as a primary clearance pathway. Although often overlooked due to the challenges of distinguishing it from biliary excretion or unabsorbed drug, intestinal excretion represents an important and underrecognized route of elimination. This session will highlight current insights and introduce predictive frameworks and tools to help researchers better identify, assess, and modulate these pathways across the drug-like chemical space.

This webinar will highlight the utility of mechanistic PBPK modeling to not only predict fetal circulatory THC concentrations but also fetal tissue THC concentrations, including in the brain. The approach outlined will provide a blueprint to develop a PBPK model to predict tissue drug exposure in any population. The audience will gain an understanding of how to identify and quantify key pathways involved in driving fetal drug exposure, determine the impact of each pathway, and incorporate them into a PBPK model to predict fetal drug exposure in both the fetal circulation as well as tissues. They will also learn how transcriptomics and proteomics can inform the effects of a drug on molecular signatures within a target tissue such as the brain.

This symposium/webinar is intended to draw attention to our recent findings (in press at Communications Biology) showing that human liver microsomes and recombinant enzymes may misidentify CYP enzymes responsible for metabolism of new drug entities. Given the potential seriousness of the inaccuracies, we would like to share this with the drug metabolism community and regulatory authorities.

Physiologically based pharmacokinetic (PBPK) modelling is an approach that utilizes the knowledge of the physiological and biological elements of the human or animal body, otherwise known as “systems data”, to predict the PK of drugs when used in conjunction with relevant compound or drug data. This involves model development of both the compound and the population of interest in a suitable PBPK platform.

Drug-drug interactions (DDIs) mediated by renal transporters such as OCT2 and MATE1/2K pose significant challenges in drug development and clinical pharmacology. Traditional approaches to assess DDI risk often rely on in vitro inhibition data and clinical studies using probe drugs. However, recent advances, including the use of endogenous biomarkers, extended clearance concepts, and physiologically based pharmacokinetic (PBPK) modeling, offer promising alternatives for early prediction and mechanistic understanding of transporter-mediated DDIs.