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This study characterised the pharmacokinetics of imatinib, nilotinib and ponatinib, focusing on perivascular adipose tissue (PVAT) accumulation and vascular toxicity in C57BL\/6 mice. Ponatinib showed unique pharmacokinetics with high apparent mean residence time (5.22\u2009h vs. 1.51\u2009h for imatinib, and 3.20\u2009h for nilotinib) and high apparent distribution volume (2891.33\u2009mL\/kg vs. 683.75\u2009mL\/kg for imatinib, and 74.84\u2009mL\/kg for nilotinib). Importantly, ponatinib had exceptionally high tissue\u2010to\u2010plasma ratio in aorta with PVAT (8.44 vs. 0.37 for imatinib, and 0.14 for nilotinib). Chronic ponatinib treatment (10\u2009mg\/kg, 4\u2009weeks) severely impaired endothelium\u2010dependent vasodilation assessed by magnetic resonance imaging in\u00a0vivo (thoracic aorta \u22127.4\u2009\u00b1\u20091.1% vs. controls 5.1\u2009\u00b1\u20091.3%). Ponatinib accumulated in aorta with PVAT after chronic treatment and directly impaired adipocyte maturation in in\u00a0vitro experiments. In isolated aorta, ponatinib reduced vascular nitric oxide (NO) release. In conclusion, endothelial dysfunction and impaired NO\u2010dependent function induced by ponatinib were related to a unique profile of ponatinib distribution compared with other TKIs, along with direct effects on adipocyte maturation. Our results suggest that after chronic treatment, ponatinib accumulation in PVAT leads to the impairment of the vasoprotective function of PVAT, contributing to endothelial dysfunction induced by ponatinib.<\/jats:p>","DOI":"10.1111\/bcpt.70181","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T02:50:00Z","timestamp":1771555800000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacokinetic Determinants of Ponatinib\u2010Induced Vascular Toxicity: A Possible Role of Perivascular Adipose Tissue"],"prefix":"10.1111","volume":"138","author":[{"given":"Iwaine","family":"Benbouziane","sequence":"first","affiliation":[{"name":"Jagiellonian Centre for Experimental Therapeutics (JCET) Jagiellonian University  Krakow Poland"},{"name":"Doctoral School of Exact and Natural Sciences Jagiellonian University  Krakow 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