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.

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.

This seminar aligns with addressing the questions and concerns early stages of a research career, emphasizing how early investigators craft a coherent scholarly identity while navigating institutional structures, mentorship, and funding ecosystems.

This webinar aims to introduce novel research on emerging transporters and their potential involvement in disease modulation and treatment. This includes characterizing the activity of OCTN1 and LAT1 in the brain and spinal cord, the role of these transporters in influencing the efficacious exposure of ergothionine and pregabalin and their therapeutic effect in preclinical mice models of Alzheimer's Disease and cold allodynia, respectively.

Pregnane X receptor (PXR) transcriptionally induces drug-metabolizing enzymes such as CYP3A4/5 to control drug metabolism, and might cause drug-drug interactions, toxicities, and resistance. Therefore, inhibitors of PXR and CYP3A4/5 might have therapeutic value. Many drugs bind to and activate PXR, and CYP3A4/5 metabolize 50% of the marketed drugs. The large and dynamic ligand binding pockets of PXR, CYP3A4, and CYP3A5 enable their promiscuous accommodation of structurally diverse ligands, and present challenges to selectively modulate them. We take structural, chemical and pharmacological approaches to selectively modulate PXR and CYP3A4/5. Our efforts provide effective approaches and novel chemical probes (e.g., inhibitors of PXR, CYP3A4 and CYP3A5) to selectively modulate the promiscuous drug metabolism pathway.

Accurately modeling complex drug-drug interactions (DDIs), including those involving non-CYP3A4 pathways, and underestimation of clearance predictions for substrates of aldehyde oxidase (AO) remain as challenges in drug development. In this webinar, Diane Ramsden will present compelling data showcasing quantitative predictions of enzyme and transporter induction including a promising application involving accurate derivation of steady-state AUC changes stemming from complex DDIs including simultaneous induction and inhibition. While , Stephanie Piekos will showcase data demonstrating improved intrinsic clearance predictions for compounds metabolized by AO, highlighting sustained, enhanced enzyme activity over extended culture periods as a new strategy for predicting AO-mediated metabolism. Together, these insights demonstrate how an advanced in vitro hepatic model can address distinct but complementary gaps in translational pharmacokinetics. Moderated by Edward LeCluyse.