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This is, among others, driven by a poor understanding of the contributive role of drug transport across biological barriers to target-site exposure.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Here, we systematically investigated the transport of 11 small-molecule drugs, both, associated and not with CIPN development, at conventional (dorsal root ganglia, sciatic nerve) and non-conventional (brain, spinal cord, skeletal muscle) CIPN sites. We developed a Combinatory Mapping Approach for CIPN, CMA-CIPN, combining in vivo and in vitro elements.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Using CMA-CIPN, we determined the unbound tissue-to-plasma concentration ratio (K<jats:sub>p,uu<\/jats:sub>) and the unbound intracellular-to-extracellular concentration ratio (K<jats:sub>p,uu,cell<\/jats:sub>), to quantitatively assess the extent of unbound drug transport across endothelial interfaces and parenchymal cellular barriers of investigated CIPN-sites, respectively, in a rat model. The analysis revealed that unique pharmacokinetic characteristics underly time-dependent accumulation of the CIPN-positive drugs paclitaxel and vincristine at conventional (dorsal root ganglia and sciatic nerve) and non-conventional (skeletal muscle) CIPN sites. Investigated CIPN-positive drugs displayed intracellular accumulation contrary to CIPN-negative drugs nilotinib and methotrexate, which lacked this feature in all investigated tissues.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Hence, high unbound drug intracellular and extracellular exposure at target sites, driven by an interplay of drug transport across the endothelial and parenchymal cellular barriers, is a predisposing factor to CIPN development for CIPN-positive drugs. Critical drug-specific features of unbound drug disposition at various CIPN- sites provide invaluable insights into understanding the pharmacological\/toxicological effects at the target-sites which will inform new strategies for monitoring and treatment of CIPN.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12987-024-00519-7","type":"journal-article","created":{"date-parts":[[2024,2,8]],"date-time":"2024-02-08T14:03:42Z","timestamp":1707401022000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Analysis of the contributing role of drug transport across biological barriers in the development and treatment of chemotherapy-induced peripheral neuropathy"],"prefix":"10.1186","volume":"21","author":[{"given":"Yang","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milda","family":"Girdenyt\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lieke","family":"Roest","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iida","family":"Liukkonen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Siskou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frida","family":"B\u00e4llgren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margareta","family":"Hammarlund-Udenaes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irena","family":"Loryan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,8]]},"reference":[{"issue":"12","key":"519_CR1","doi-asserted-by":"publisher","first-page":"2461","DOI":"10.1016\/j.pain.2014.09.020","volume":"155","author":"M Seretny","year":"2014","unstructured":"Seretny M, Currie GL, Sena ES, Ramnarine S, Grant R, MacLeod MR, et al. 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