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Anlotinib is approved for the treatment of chemotherapy\u2010refractory or metastatic non\u2010small cell lung cancer; its clinical application is limited by severe adverse reactions, particularly hypertension and diarrhea, and the relationship between intracellular exposure and toxicity remains unclear. In this study, a rapid and sensitive UHPLC\u2013MS\/MS method was developed using an Agilent 1290\u20106460A ultra\u2010high performance liquid chromatography coupled to a triple quadrupole mass spectrometer to quantify anlotinib in human intestinal epithelial cells (HIECs) and human umbilical vein endothelial cells (HUVECs). Pazopanib\u2010d3 was employed as an internal standard, and anlotinib was accurately quantified in 10\u20134000\u2009ng\/mL in positive ionization mode, with acceptable specificity, linearity, accuracy, precision, stability, and dilution integrity. The method was successfully applied to determine intracellular and extracellular anlotinib concentrations in HIECs and HUVECs. Notably, significant differences were observed between intracellular and extracellular concentrations, and intracellular anlotinib concentrations, rather than extracellular concentrations, were positively correlated with cytotoxicity in both cell types. Collectively, this study established a robust analytical approach for intracellular anlotinib quantification and provided experimental evidence linking intracellular exposure to cytotoxicity, offering a foundation for further investigation of anlotinib\u2010induced adverse reactions.<\/jats:p>","DOI":"10.1002\/bmc.70373","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T10:24:01Z","timestamp":1769595841000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An LC\u2013MS\/MS\u2010Based Quantification of Intracellular Anlotinib Reveals Exposure\u2013Toxicity Relationships in Endothelial and Intestinal Epithelial Cells"],"prefix":"10.1002","volume":"40","author":[{"given":"Zhenhui","family":"Jiang","sequence":"first","affiliation":[{"name":"College of Traditional Chinese Medicine Yunnan University of Chinese Medicine  Kunming Yunnan China"},{"name":"Department of Pharmacy Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital)  Shanghai P. 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