{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T19:34:34Z","timestamp":1790192074691,"version":"4.1.0"},"reference-count":27,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2020,4,28]],"date-time":"2020-04-28T00:00:00Z","timestamp":1588032000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the CAMS Innovation Fund for Medical Sciences","award":["2017-I2M-1-005, 2016-I2M-1-001 and 2017-I2M-1-003"],"award-info":[{"award-number":["2017-I2M-1-005, 2016-I2M-1-001 and 2017-I2M-1-003"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2020,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>To clarify the distribution of lorlatinib in the brain and elucidate the molecular\u00a0mechanisms of lorlatinib penetration across the blood\u2010brain barrier (BBB).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Cytological experiments were performed to investigate the growth inhibitory effect of lorlatinib on different cells (endothelial cells HUVEC, HMEC\u20101, and HCMEC\/D3) and to investigate the protective effect of lorlatinib on neuronal cells after SH\u2010SY5Y hypoxia\/reoxygenation injury. Furthermore, rat brain tissue was sequenced, and the differentially expressed genes (secreted phosphoprotein 1 (SPP1), vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF\u2010\u03b2), Claudin, ZO\u20101 and P\u2010gp) in several different drug treatment groups were verified by Real\u2010Time PCR. Lorlatinib brain distribution was predicted by physiologically based pharmacokinetics (PBPK).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Lorlatinib and crizotinib both had inhibitory effects on endothelial cells, however lorlatinib inhibited the growth of HCMEC\/D3 more efficaciously than crizotinib. In the SH\u2010SY5Y hypoxia model, lorlatinib had a greater protective effect on nerve cell damage caused by hypoxia and reoxygenation than crizotinib. The expression of SPP1, VEGF, TGF\u2010\u03b2, and Claudin in brain tissue was significantly downregulated after lorlatinib administration, and the expression level of early growth transcription factor 1 (Egr\u20101) was significantly increased. The PBPK model successfully described lorlatinib concentrations in blood and brain tissue in the mouse model and gave a brain tissue partition coefficient of 0.7.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Lorlatinib can increase the permeability of the blood\u2010brain barrier whereby we suggest its underlying working mechanism is related to downregulating SPP1, inhibiting VEGF, TGF\u2010\u03b2, and Claudin subsequently reducing the number of tight junctions between BBB cells. Lorlatinib plays a protective role on injured nerve cells and does not change the amount of P\u2010gp expression in brain tissue, which may be important for its ability to be efficacious across the BBB with a low incidence of resistance.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.3061","type":"journal-article","created":{"date-parts":[[2020,4,29]],"date-time":"2020-04-29T01:51:51Z","timestamp":1588125111000},"page":"4350-4359","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["The underlying mechanisms of lorlatinib penetration across the blood<i>\u2010<\/i>brain barrier and the distribution characteristics of lorlatinib in the brain"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4015-6021","authenticated-orcid":false,"given":"Wei","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Pharmacy National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dujia","family":"Jin","sequence":"additional","affiliation":[{"name":"Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2830-217X","authenticated-orcid":false,"given":"Yafei","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pharmacy National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guohui","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacy National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 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