Sublethal stress from polypharmacy modulates scavenging function and fenestrations in mouse liver sinusoidal...

Polypharmacy, the concurrent use of multiple medications, is increasingly prevalent in older people and is associated with adverse outcomes such as falls, frailty, functional, and cognitive decline, and increased hospitalization and mortality. The liver, as the primary site of metabolism, is exposed to varying drug concentrations during first pass metabolism, hepatic clearance and perfusion, potentially causing alterations in liver sinusoidal endothelial cells (LSEC). LSEC are specialized endothelial cells responsible for maintaining fenestrations-dynamic, transcellular pores that facilitate the exchange of substances between the blood and liver parenchyma. Disruption of fenestrations can compromise liver function, contributing to a variety of hepatic disorders. This study investigated the effects of 4 commonly prescribed drugs-metoprolol, citalopram, oxybutynin, and oxycodone-on LSEC function. We examined their impact on LSEC viability, endocytosis, and fenestration morphology at both systemic steady-state and first-pass concentrations, separately and in a polypharmacy cocktail to model clinical exposure. All treatments induced sublethal metabolic changes, but effects on LSEC functions were drug- and concentration-dependent. Citalopram and oxybutynin caused dose-dependent defenestration, whereas metoprolol and oxycodone produced mild, nondose-dependent effects. Endocytic activity was increased with oxybutynin, metoprolol, oxycodone, and the polypharmacy cocktail, whereas citalopram had no effect. The polypharmacy cocktail triggered synergistic defenestration at first-pass concentrations, but not at steady-state levels. These results highlight the concentration-dependent and combinatorial effects of polypharmacy on LSECs, emphasizing the need to consider endothelial responses in drug safety and pharmacokinetic assessments, particularly in patients exposed to multiple medications. SIGNIFICANCE STATEMENT: Polypharmacy is increasingly common, however, its effects on liver sinusoidal endothelial cells remain poorly understood. Using in vitro models, this study shows that drug combinations can induce sublethal functional and structural alterations in these cells, highlighting endothelial dysfunction as a potential early mechanism contributing to drug-induced liver impairment.