The workshop is neither trying to provide a 101 course on LC-MS proteomics nor attempts to focus on what is new in LC-MS proteomics techniques. Attendees need to have some background but not necessarily leading experts in the field. The consensus report from the previous ISSX Workshop held in 2018 (Prasad et al. 2019, Clinical Pharmacology and Therapeutics) is considered a background reading. The recent Symposium Repot from North American ISSX 2023 in Boston (Prasad et al 2024, Drug Metabolism Disposition, In Press) captures the content of lectures and workshop exercises. Hence, the event builds on what is known in the literature in relation to LC-MS proteomics and provides more practical guidance for those who are expanding their research activities in this area, such that they do not go through pitfalls and get to the end point faster.

Biotransformation science is critical to understanding the metabolic fate, pharmacokinetics, safety, and efficacy of new therapeutics. Biotransformation Stories highlights emerging research from doctoral trainees applying both established and evolving approaches to drug and xenobiotic metabolism. Emily Gracey will explore advanced human in vitro models for studying drug metabolism and toxicology, including 3D cultures, organoids, induced pluripotent stem cell-derived models, and microphysiological systems. These technologies offer opportunities to better recapitulate human physiology, improve preclinical translation, and complement conventional 2D cultures and animal models. Ian Levasseur’s presentation will examine the metabolism of BKI-1708, a promising anti-Cryptosporidium agent that forms an unusual, pharmacologically active hemiaminal metabolite. Using human liver microsomes, selective CYP inhibition, recombinant enzymes, and LC-MS/MS, CYP2C8 was identified as the primary enzyme responsible for metabolite formation, illustrating how mechanistic biotransformation studies can inform pharmacokinetics and drug–drug interaction risk. These stories will showcase how emerging scientists are addressing contemporary biotransformation challenges and provide a forum for engagement between academic trainees and industrial DMPK scientists.

The substitution of hydrogen with deuterium — a stable, non-radioactive isotope — represents a subtle and mechanistically powerful strategy in modern drug discovery. This webinar will introduce DMPK scientists and medicinal chemists to the kinetic isotope effect (KIE), exploring the physicochemical basis by which the stronger C–D bond can attenuate drug metabolism and influence a compound's pharmacokinetic profile. Drawing on both preclinical and clinical examples, attendees will gain an appreciation for how deuterium incorporation can be leveraged in drug design and as a mechanistic probe for identifying the site of metabolism. The presentation will also address the limitations of this approach — including metabolic switching and when to expect scenarios where no isotope effect is observed. Attendees will leave with a practical, foundational framework for evaluating when and how deuterium substitution can be a meaningful tool in their DMPK and medicinal chemistry toolkit.

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.