Quantitative Modeling of Lipid Droplet Contribution to Intracellular Drug Distribution and Efficacy of Tyrosine Kinase Inhibitors

Lipid droplets (LDs) are dynamic organelles that influence intracellular drug disposition, yet their role in modulating therapeutic efficacy remains poorly defined. This study integrates experimental cytotoxicity assays with a mechanistic subcellular pharmacokinetic (PK) model to investigate how LD dynamics affect the distribution and activity of tyrosine kinase inhibitors (TKIs). The model, based on physicochemical parameters including logP, pKa, and protein binding, revealed that increases in LD volume sequester lipophilic drugs such as abemaciclib and lapatinib, reducing their cytoplasmic concentrations and efficacy, whereas low logP compounds like palbociclib remain largely unaffected. TKIs with high pKa values, such as sunitinib, preferentially accumulate in lysosomes, consistent with model predictions and experimental imaging results. Cytotoxicity assays confirmed the predicted bidirectional effects of LD expansion and depletion on drug efficacy. These findings identify LDs as active modulators of subcellular drug PK and suggest that targeting LD dynamics may enhance the therapeutic performance of lipophilic TKIs, especially in cancers with dysregulated lipid metabolism.