{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T12:40:39Z","timestamp":1793364039462,"version":"4.5.0"},"reference-count":70,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2023,7,13]],"date-time":"2023-07-13T00:00:00Z","timestamp":1689206400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,7,13]],"date-time":"2023-07-13T00:00:00Z","timestamp":1689206400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["848068"],"award-info":[{"award-number":["848068"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pharm Res"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Introduction<\/jats:title>\n                <jats:p>The unbound brain extracelullar fluid (brain<jats:sub>ECF<\/jats:sub>) to plasma steady state partition coefficient, K<jats:sub>p,uu,BBB<\/jats:sub>, values provide steady-state information on the extent of blood-brain barrier (BBB) transport equilibration, but not on pharmacokinetic (PK) profiles seen by the brain targets. Mouse models are frequently used to study brain PK, but this information cannot directly be used to inform on human brain PK, given the different CNS physiology of mouse and human. Physiologically based PK (PBPK) models are useful to translate PK information across species.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Aim<\/jats:title>\n                <jats:p>Use the LeiCNS-PK3.0 PBPK model, to predict brain extracellular fluid PK in mice.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Information on mouse brain physiology was collected from literature. All available connected data on unbound plasma, brain<jats:sub>ECF<\/jats:sub> PK of 10 drugs (cyclophosphamide, quinidine, erlotonib, phenobarbital, colchicine, ribociclib, topotecan, cefradroxil, prexasertib, and methotrexate) from different mouse strains were used. Dosing regimen dependent plasma PK was modelled, and Kpuu,BBB values were estimated, and provided as input into the LeiCNS-PK3.0 model to result in prediction of PK profiles in brain<jats:sub>ECF<\/jats:sub>.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Overall, the model gave an adequate prediction of the brain<jats:sub>ECF<\/jats:sub> PK profile for 7 out of the 10 drugs. For 7 drugs, the predicted versus observed brain<jats:sub>ECF<\/jats:sub> data was within two-fold error limit and the other 2 drugs were within five-fold error limit.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>The current version of the mouse LeiCNS-PK3.0 model seems to reasonably predict available information on brain<jats:sub>ECF<\/jats:sub> from healthy mice for most drugs. This brings the translation between mouse and human brain PK one step further.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s11095-023-03554-5","type":"journal-article","created":{"date-parts":[[2023,7,13]],"date-time":"2023-07-13T20:29:57Z","timestamp":1689280197000},"page":"2555-2566","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Using the LeiCNS-PK3.0 Physiologically-Based Pharmacokinetic Model to Predict Brain Extracellular Fluid Pharmacokinetics in Mice"],"prefix":"10.1007","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0517-6051","authenticated-orcid":false,"given":"Mohammed A. A.","family":"Saleh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8954-882X","authenticated-orcid":false,"given":"Berfin","family":"G\u00fclave","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6348-8910","authenticated-orcid":false,"given":"Olivia","family":"Campagne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1546-9720","authenticated-orcid":false,"given":"Clinton F.","family":"Stewart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3333-861X","authenticated-orcid":false,"given":"Jeroen","family":"Elassaiss-Schaap","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8303-1117","authenticated-orcid":false,"given":"Elizabeth C. M.","family":"de Lange","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,7,13]]},"reference":[{"key":"3554_CR1","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.ejim.2016.11.013","volume":"39","author":"S Garattini","year":"2017","unstructured":"Garattini S, Grignaschi G. Animal testing is still the best way to find new treatments for patients. Eur J Intern Med. 2017;39:32\u20135. https:\/\/doi.org\/10.1016\/j.ejim.2016.11.013.","journal-title":"Eur J Intern Med."},{"key":"3554_CR2","doi-asserted-by":"publisher","unstructured":"Murillo-Cuesta S, Artuch R, Asensio F, de la Villa P, Dierssen M, Enr\u00edquez JA, Fillat C, Fourcade S, Ib\u00e1\u00f1ez B, Montoliu L, Oliver E, Pujol A, Salido E, Vallejo M, Varela-Nieto I. The value of mouse models of rare diseases: A spanish experience. Front Genet. 2020; 11: 583932. https:\/\/doi.org\/10.3389\/fgene.2020.583932.","DOI":"10.3389\/fgene.2020.583932."},{"key":"3554_CR3","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.brainresbull.2011.11.017","volume":"88","author":"AM Hall","year":"2012","unstructured":"Hall AM, Roberson ED. Mouse models of Alzheimer\u2019s disease. Brain Res Bull. 2012;88:3\u201312. https:\/\/doi.org\/10.1016\/j.brainresbull.2011.11.017.","journal-title":"Brain Res Bull."},{"key":"3554_CR4","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1023\/a:1016207208406","volume":"12","author":"ECM de Lange","year":"1995","unstructured":"de Lange ECM, Hesselink MB, Danhof M, de Boer AG, Breimer DD. The use of intracerebral microdialysis to determine changes in blood-brain barrier transport characteristics. Pharm Res. 1995;12:129\u201333. https:\/\/doi.org\/10.1023\/a:1016207208406.","journal-title":"Pharm Res."},{"key":"3554_CR5","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1007\/s11095-022-03172-7","volume":"39","author":"SG Summerfield","year":"2022","unstructured":"Summerfield SG, Yates JWT, Fairman DA. Free drug theory \u2013 no longer just a hypothesis? Pharm Res. 2022;39:213\u201322. https:\/\/doi.org\/10.1007\/s11095-022-03172-7.","journal-title":"Pharm. Res."},{"key":"3554_CR6","unstructured":"de Lange ECM, Hesselink MB, Danhof M, de Boer AG, Breimer DD. The use of intracerebral microdialysis to determine changes in blood-brain barrier transport characteristics 1995b."},{"key":"3554_CR7","doi-asserted-by":"publisher","first-page":"612","DOI":"10.18433\/JPPS30608","volume":"22","author":"O Campagne","year":"2019","unstructured":"Campagne O, Davis A, Zhong B, Nair S, Haberman V, Patel YT, Janke L, Roussel MF, Stewart CF. Cns penetration of cyclophosphamide and metabolites in mice bearing group 3 medulloblastoma and non-tumor bearing mice. J Pharm Pharm Sci. 2019;22:612\u201329. https:\/\/doi.org\/10.18433\/JPPS30608.","journal-title":"J Pharm Pharm Sci."},{"key":"3554_CR8","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/S0169-409X(00)00109-5","volume":"45","author":"M Hammarlund-Udenaes","year":"2000","unstructured":"Hammarlund-Udenaes M. The use of microdialysis in CNS drug delivery studies: Pharmacokinetic perspectives and results with analgesics and antiepileptics. Adv Drug Deliv Rev. 2000;45:283\u201394. https:\/\/doi.org\/10.1016\/S0169-409X(00)00109-5.","journal-title":"Adv Drug Deliv Rev."},{"key":"3554_CR9","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1007\/s00280-019-03864-9","volume":"84","author":"YT Patel","year":"2019","unstructured":"Patel YT, Davis A, Baker SJ, Campagne O, Stewart CF. CNS penetration of the CDK4\/6 inhibitor ribociclib in non-tumor bearing mice and mice bearing pediatric brain tumors. Cancer Chemother Pharmacol. 2019;84:447\u201352. https:\/\/doi.org\/10.1007\/s00280-019-03864-9.","journal-title":"Cancer Chemother Pharmacol."},{"key":"3554_CR10","doi-asserted-by":"publisher","unstructured":"Perkins RS, Davis A, Campagne O, Owens TS, Stewart CF. CNS penetration of methotrexate and its metabolite 7-hydroxymethotrexate in mice bearing orthotopic Group 3 medulloblastoma tumors and model-based simulations for children. Drug Metab Pharmacokinet 2022; 100471. https:\/\/doi.org\/10.1016\/j.dmpk.2022.100471.","DOI":"10.1016\/j.dmpk.2022.100471."},{"key":"3554_CR11","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.ejps.2013.12.020","volume":"57","author":"J Westerhout","year":"2014","unstructured":"Westerhout J, Van Den Berg DJ, Hartman R, Danhof M, De Lange ECM. Prediction of methotrexate CNS distribution in different species - Influence of disease conditions. Eur J Pharm Sci. 2014;57:11\u201324. https:\/\/doi.org\/10.1016\/j.ejps.2013.12.020.","journal-title":"Eur J Pharm Sci."},{"key":"3554_CR12","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1007\/s11095-016-2065-3","volume":"34","author":"Y Yamamoto","year":"2017","unstructured":"Yamamoto Y, V\u00e4litalo PA, van den Berg DJ, Hartman R, van den Brink W, Wong YC, Huntjens DR, Proost JH, Vermeulen A, Krauwinkel W, Bakshi S, Aranzana-Climent V, Marchand S, Dahyot-Fizelier C, Couet W, Danhof M, van Hasselt JGC, de Lange ECM. A Generic Multi-Compartmental CNS Distribution Model Structure for 9 Drugs Allows Prediction of Human Brain Target Site Concentrations. Pharm Res. 2017;34:333\u201351. https:\/\/doi.org\/10.1007\/s11095-016-2065-3.","journal-title":"Pharm Res."},{"key":"3554_CR13","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1007\/s10928-021-09768-7","volume":"48","author":"MAA Saleh","year":"2021","unstructured":"Saleh MAA, Loo CF, Elassaiss-Schaap J, De Lange ECM. Lumbar cerebrospinal fluid-to-brain extracellular fluid surrogacy is context-specific: insights from LeiCNS-PK3.0 simulations. J Pharmacokinet Pharmacodyn. 2021;48:725\u201341. https:\/\/doi.org\/10.1007\/s10928-021-09768-7.","journal-title":"J Pharmacokinet Pharmacodyn."},{"key":"3554_CR14","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/j.ejps.2017.11.011","volume":"112","author":"Y Yamamoto","year":"2018","unstructured":"Yamamoto Y, V\u00e4litalo PA, Wong YC, Huntjens DR, Proost JH, Vermeulen A, Krauwinkel W, Beukers MW, Kokki H, Kokki M, Danhof M, van Hasselt JGC, de Lange ECM. Prediction of human CNS pharmacokinetics using a physiologically-based pharmacokinetic modeling approach. Eur J Pharm Sci. 2018;112:168\u201379. https:\/\/doi.org\/10.1016\/j.ejps.2017.11.011.","journal-title":"Eur J Pharm Sci."},{"key":"3554_CR15","doi-asserted-by":"publisher","first-page":"D1074","DOI":"10.1093\/nar\/gkx1037","volume":"46","author":"DS Wishart","year":"2017","unstructured":"Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Iynkkaran NAI, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucl Acids Res. 2017;46:D1074\u201382.","journal-title":"Nucl Acids. Res."},{"key":"3554_CR16","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1002\/jps","volume":"98","author":"R Mannhold","year":"2009","unstructured":"Mannhold R, Poda GI, Ostermann C, Tetko IV. Calculation of molecular lipophilicity: state-of-the-art and comparison of logp methods on more than 96,000 compounds. J Pharm Sci. 2009;98:861\u201393. https:\/\/doi.org\/10.1002\/jps.","journal-title":"J Pharm Sci."},{"key":"3554_CR17","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1021\/ci100019p","volume":"50","author":"J Manchester","year":"2010","unstructured":"Manchester J, Walkup G, Rivin O, You Z. Evaluation of pka estimation methods on 211 druglike compounds. J Chem Inf Model. 2010;50:565\u201371. https:\/\/doi.org\/10.1021\/ci100019p.","journal-title":"J. Chem Inf Model."},{"key":"3554_CR18","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1177\/1087057112468156","volume":"18","author":"I Szir\u00e1ki","year":"2013","unstructured":"Szir\u00e1ki I, Erdo F, Trampus P, Sike M, Moln\u00e1r PM, Rajnai Z, Moln\u00e1r J, Wilhelm I, Fazakas C, Kis E, Krizbai I, Krajcsi P. The use of microdialysis techniques in mice to study P-gp function at the blood-brain barrier. J Biomol Screen. 2013;18:430\u201340.","journal-title":"J Biomol Screen"},{"key":"3554_CR19","first-page":"816","volume":"245","author":"DR Jones","year":"1988","unstructured":"Jones DR, Hall SD, Jackson EK, Branch RA, Wilkinson GR. Brain uptake of benzodiazepines: Effects of lipophilicity and plasma protein binding. J Pharmacol Exp Ther. 1988;245:816\u201322.","journal-title":"J Pharmacol Exp Ther"},{"key":"3554_CR20","doi-asserted-by":"publisher","unstructured":"Pierre A. Evrard, Corinne Ragusi, Gabrielle Boschi, Roger K. Verbeeck, Jean-Michel Scherrmann (1998) Simultaneous microdialysis in brain and blood of the mouse: extracellular and intracellular brain colchicine disposition. Brain Res. 786(1-2):122\u20137. https:\/\/doi.org\/10.1016\/S0006-8993(97)01454-6.","DOI":"10.1016\/S0006-8993(97)01454-6"},{"key":"3554_CR21","doi-asserted-by":"publisher","unstructured":"Chen X, Keep RF, Liang Y, Zhu H-J, Hammarlund-Udenaes M, Hu Y, Smith DE. Influence of peptide transporter 2 (PEPT2) on the distribution of cefadroxil in mouse brain: A microdialysis study. Biochem Pharmacol. 2017:13189\u201397. https:\/\/doi.org\/10.1016\/j.bcp.2017.02.005.","DOI":"10.1016\/j.bcp.2017.02.005"},{"key":"3554_CR22","doi-asserted-by":"publisher","first-page":"105106","DOI":"10.1016\/j.ejps.2019.105106","volume":"142","author":"O Campagne","year":"2020","unstructured":"Campagne O, Davis A, Maharaj AR, Zhong B, Stripay J, Farmer D, Roussel MF, Stewart CF. CNS penetration and pharmacodynamics of the CHK1 inhibitor prexasertib in a mouse Group 3 medulloblastoma model. Eur J Pharm Sci. 2020;142:105106. https:\/\/doi.org\/10.1016\/j.ejps.2019.105106.","journal-title":"Eur J Pharm Sci."},{"key":"3554_CR23","doi-asserted-by":"publisher","unstructured":"Bauer RJ NONMEM Users guide: Introduction to NONMEM 7.4.3, In: ICON Plc 2019. https:\/\/doi.org\/10.1017\/CBO9781107415324.004.","DOI":"10.1017\/CBO9781107415324.004."},{"key":"3554_CR24","doi-asserted-by":"publisher","first-page":"1737","DOI":"10.1007\/s11095-007-9502-2","volume":"25","author":"M Hammarlund-Udenaes","year":"2008","unstructured":"Hammarlund-Udenaes M, Frid\u00e9n M, Syv\u00e4nen S, Gupta A. On the rate and extent of drug delivery to the brain. Pharm Res. 2008;25:1737\u201350. https:\/\/doi.org\/10.1007\/s11095-007-9502-2.","journal-title":"Pharm Res."},{"key":"3554_CR25","volume-title":"R: A language and environment for statistical computing","author":"R Core Team","year":"2019","unstructured":"R Core Team. R: A language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2019."},{"key":"3554_CR26","unstructured":"Fidler M, Hallow M, Wilkins J, Wang W. RxODE: Facilities for simulating from ODE-based models 2019."},{"issue":"5","key":"3554_CR27","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1093\/cercor\/bhh165","volume":"15","author":"N Kova\u010devi\u0107","year":"2004","unstructured":"Kova\u010devi\u0107 N, Henderson JT, Chan E, Lifshitz N, Bishop J, Evans AC, Henkelman RM, Chen XJ. A threedimensional mri atlas of the mouse brain with estimates of the average and variability. Cereb Cortex. 2004;15(5):639\u201345. https:\/\/doi.org\/10.1093\/cercor\/bhh165.","journal-title":"Cereb Cortex"},{"key":"3554_CR28","doi-asserted-by":"publisher","first-page":"97","DOI":"10.3390\/pharmaceutics6010097","volume":"6","author":"RK Singh Badhan","year":"2014","unstructured":"Singh Badhan RK, Chenel M, Penny JI. Development of a physiologically-based pharmacokinetic model of the rat central nervous system. Pharmaceutics. 2014;6:97\u2013136. https:\/\/doi.org\/10.3390\/pharmaceutics6010097.","journal-title":"Pharmaceutics"},{"key":"3554_CR29","doi-asserted-by":"publisher","unstructured":"Fenneteau F, Turgeon J, Couture L, Michaud V, Li J, Nekka F. Assessing drug distribution in tissues expressing P-glycoprotein through physiologically based pharmacokinetic modeling: model structure and parameters determination Abstract. Theor Biol Medical Model. 2009;6(1). https:\/\/doi.org\/10.1186\/1742-4682-6-2.","DOI":"10.1186\/1742-4682-6-2"},{"key":"3554_CR30","doi-asserted-by":"publisher","unstructured":"Mizoguchi T, Minakuchi H, Ishisaka M, Tsuruma K, Shimazawa M, Hara H. Behavioral abnormalities with disruption of brain structure in mice overexpressing VGF Abstract. Sci Rep. 2017;7(1). https:\/\/doi.org\/10.1038\/s41598-017-04132-7.","DOI":"10.1038\/s41598-017-04132-7"},{"issue":"6","key":"3554_CR31","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1002\/cne.21090","volume":"498","author":"KL Baker","year":"2006","unstructured":"Baker KL, Daniels SB, Lennington JB, Lardaro T, Czap A, Notti RQ, Cooper O, Isacson O, Frasca S, Conover JC. Neuroblast protuberances in the subventricular zone of the regenerative MRL\/MpJ mouse. J Comp Neurol. 2006;498(6):747\u201361. https:\/\/doi.org\/10.1002\/cne.21090.","journal-title":"J Comp Neurol"},{"key":"3554_CR32","doi-asserted-by":"publisher","first-page":"2778","DOI":"10.1111\/bph.12609","volume":"171","author":"ZY Hu","year":"2014","unstructured":"Hu ZY, Lu J, Zhao Y. A physiologically based pharmacokinetic model of alvespimycin in mice and extrapolation to rats and humans. Br J Pharmacol. 2014;171:2778\u201389. https:\/\/doi.org\/10.1111\/bph.12609.","journal-title":"Br J Pharmacol."},{"issue":"4","key":"3554_CR33","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1177\/074823379701300401","volume":"13","author":"RP Brown","year":"1997","unstructured":"Brown RP, Delp MD, Lindstedt SL, Rhomberg LR, Beliles RP. Physiological parameter values for physiologically based pharmacokinetic models. Toxicol Ind Health. 1997;13(4):407\u201384. https:\/\/doi.org\/10.1177\/074823379701300401.","journal-title":"Toxicol Ind Health"},{"issue":"7","key":"3554_CR34","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1517\/17425247.2016.1171315","volume":"13","author":"WM Pardridge","year":"2016","unstructured":"Pardridge WM. CSF blood-brain barrier and brain drug delivery. Expert Opin Drug Deliv. 2016;13(7):963\u201375. https:\/\/doi.org\/10.1517\/17425247.2016.1171315.","journal-title":"Expert Opin Drug Deliv"},{"key":"3554_CR35","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1016\/j.neuroimage.2007.05.046","volume":"37","author":"A Badea","year":"2007","unstructured":"Badea A, Ali-Sharief AA, Johnson GA. Morphometric analysis of the C57BL\/6J mouse brain. Neuroimage. 2007;37:683\u201393. https:\/\/doi.org\/10.1016\/j.neuroimage.2007.05.046.","journal-title":"Neuroimage"},{"issue":"1","key":"3554_CR36","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.neuroimage.2008.03.037","volume":"42","author":"AE Dorr","year":"2008","unstructured":"Dorr AE, Lerch JP, Spring S, Kabani N, Henkelman RM. High resolution three-dimensional brain atlas using an average magnetic resonance image of 40 adult C57Bl\/6J mice. NeuroImage. 2008;42(1):60\u20139. https:\/\/doi.org\/10.1016\/j.neuroimage.2008.03.037.","journal-title":"NeuroImage"},{"key":"3554_CR37","doi-asserted-by":"publisher","first-page":"3","DOI":"10.14943\/jjvr.57.1.3","volume":"57","author":"K Hino","year":"2009","unstructured":"Hino K, Otsuka S, Ichii O, Hashimoto Y, Kon Y. Strain differences of cerebral ventricles in mice: Can the MRL\/MpJ mouse be a model for hydrocephalus? Jpn J Vet Res. 2009;57:3\u201311. https:\/\/doi.org\/10.14943\/jjvr.57.1.3.","journal-title":"Jpn J Vet Res"},{"issue":"4","key":"3554_CR38","doi-asserted-by":"publisher","first-page":"196","DOI":"10.3390\/fluids4040196","volume":"4","author":"LA Ray","year":"2019","unstructured":"Ray LA, Heys JJ. Fluid flow and mass transport in brain tissue. Fluids. 2019;4(4):196. https:\/\/doi.org\/10.3390\/fluids4040196.","journal-title":"Fluids"},{"issue":"3","key":"3554_CR39","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/0165-0270(82)90088-7","volume":"6","author":"RA Rudick","year":"1982","unstructured":"Rudick RA, Zirretta DK, Herndon RM. Clearance of albumin from mouse subarachnoid space: a measure of CSF bulk flow. J Neurosci Methods. 1982;6(3):253\u20139. https:\/\/doi.org\/10.1016\/0165-0270(82)90088-7.","journal-title":"J Neurosci Methods"},{"key":"3554_CR40","doi-asserted-by":"publisher","unstructured":"Matthew J., Simon Jeffrey J., Iliff (2016) Regulation of cerebrospinal fluid (CSF) flow in neurodegenerative neurovascular and neuroinflammatory disease BBA-Mol Basis Dis 1862(3) 442-451. https:\/\/doi.org\/10.1016\/j.bbadis.2015.10.014.","DOI":"10.1016\/j.bbadis.2015.10.014"},{"key":"3554_CR41","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fphys.2019.00233","volume":"10","author":"AF Smith","year":"2019","unstructured":"Smith AF, Doyeux V, Berg M, Peyrounette M, Haft-Javaherian M, Larue AE, Slater JH, Lauwers F, Blinder P, Tsai P, Kleinfeld D, Schaffer CB, Nishimura N, Davit Y, Lorthois S. Brain capillary networks across species: A few simple organizational requirements are sufficient to reproduce both structure and function. Front Physiol. 2019;10:1\u201322. https:\/\/doi.org\/10.3389\/fphys.2019.00233.","journal-title":"Front Physiol."},{"key":"3554_CR42","doi-asserted-by":"publisher","first-page":"1211","DOI":"10.1152\/jappl.1999.86.4.1211","volume":"86","author":"JA Boero","year":"1999","unstructured":"Boero JA, Ascher J, Arregui A, Rovainen C, Woolsey TA. Increased brain capillaries in chronic hypoxia. J Appl Physiol. 1999;86:1211\u20139. https:\/\/doi.org\/10.1152\/jappl.1999.86.4.1211.","journal-title":"J Appl Physiol."},{"issue":"3","key":"3554_CR43","doi-asserted-by":"publisher","first-page":"e0236770","DOI":"10.1371\/journal.pone.0236770","volume":"16","author":"MS Thomsen","year":"2021","unstructured":"Thomsen MS, Humle N, Hede E, Moos T, Burkhart A, Thomsen LB. The bloodbrain barrier studied in vitro across species. PLOS One. 2021;16(3):e0236770. https:\/\/doi.org\/10.1371\/journal.pone.0236770.","journal-title":"PLOS One"},{"key":"3554_CR44","doi-asserted-by":"publisher","unstructured":"Janiurek MM, Soylu-Kucharz R, Christoffersen C, Kucharz K, Lauritzen M. Apolipoprotein M-bound sphingosine-1-phosphate regulates blood\u2013brain barrier paracellular permeability and transcytosis. eLife. 2019;8 https:\/\/doi.org\/10.7554\/eLife.49405.","DOI":"10.7554\/eLife.49405"},{"key":"3554_CR45","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1002\/(SICI)1520-6017(200001)89:13.0.CO;2-E","volume":"89","author":"P Poulin","year":"2000","unstructured":"Poulin P, Theil FP. A priori prediction of tissue: Plasma partition coefficients of drugs to facilitate the use of physiologically-based pharmacokinetic models in drug discovery. J Pharm Sci. 2000;89:16\u201335. https:\/\/doi.org\/10.1002\/(SICI)1520-6017(200001)89:13.0.CO;2-E.","journal-title":"J Pharm Sci"},{"key":"3554_CR46","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/j.resp.2011.11.015","volume":"180","author":"NK Iversen","year":"2012","unstructured":"Iversen NK, Malte H, Baatrup E, Wang T. The normal acid-base status of mice. Respir Physiol Neurobiol. 2012;180:252\u20137. https:\/\/doi.org\/10.1016\/j.resp.2011.11.015.","journal-title":"Respir Physiol Neurobiol"},{"key":"3554_CR47","doi-asserted-by":"publisher","unstructured":"Tyrtyshnaia AA, Lysenko LV, Madamba F, Manzhulo IV, Khotimchenko MY, Kleschevnikov AM. Acute neuroinflammation provokes intracellular acidification in mouse hippocampus. J Neuroinflammation. 2016;13(1). https:\/\/doi.org\/10.1186\/s12974-016-0747-8.","DOI":"10.1186\/s12974-016-0747-8"},{"issue":"5","key":"3554_CR48","doi-asserted-by":"publisher","first-page":"1079","DOI":"10.1038\/sj.emboj.7600576","volume":"24","author":"D Kasper","year":"2005","unstructured":"Kasper D, Planells-Cases R, Fuhrmann JC, Scheel O, Zeitz O, Ruether K, Schmitt A, Po\u00ebt M, Steinfeld R, Schweizer M, Kornak U, Jentsch TJ. Loss of the chloride channel ClC-7 leads to lysosomal storage disease and neurodegeneration. The EMBO Journal. 2005;24(5):1079\u201391. https:\/\/doi.org\/10.1038\/sj.emboj.7600576.","journal-title":"The EMBO Journal"},{"key":"3554_CR49","doi-asserted-by":"publisher","first-page":"1490","DOI":"10.1091\/mbc.E06","volume":"18","author":"A Majumdar","year":"2007","unstructured":"Majumdar A, Cruz D, Asamoah N, Buxbaum A, Sohar I, Lobel P, Maxfield FR. Activation of microglia acidifies lysosomes and leads to degradation of alzheimer amyloid fibrils. Mol Biol Cell. 2007;18:1490\u20136. https:\/\/doi.org\/10.1091\/mbc.E06.","journal-title":"Mol Biol Cell"},{"key":"3554_CR50","doi-asserted-by":"publisher","unstructured":"Pla A, Pascual M, Consuelo G. Autophagy constitutes a protective mechanism against ethanol toxicity in mouse astrocytes and neurons. PLOS One 2016;11(4) e0153097. https:\/\/doi.org\/10.1371\/journal.pone.0153097.","DOI":"10.1371\/journal.pone.0153097"},{"issue":"21","key":"3554_CR51","doi-asserted-by":"publisher","first-page":"6013","DOI":"10.1093\/hmg\/ddv314","volume":"24","author":"AG Henry","year":"2015","unstructured":"Henry AG, Aghamohammadzadeh S, Samaroo H, Chen Y, Mou K, Needle E, Hirst WD. Pathogenic LRRK2 mutations through increased kinase activity produce enlarged lysosomes with reduced degradative capacity and increase ATP13A2 expression. Hum Mol Genet. 2015;24(21):6013\u201328. https:\/\/doi.org\/10.1093\/hmg\/ddv314.","journal-title":"Hum Mol Genet"},{"issue":"34","key":"3554_CR52","doi-asserted-by":"publisher","first-page":"11485","DOI":"10.1523\/JNEUROSCI.0210-14.2014","volume":"34","author":"M Bae","year":"2014","unstructured":"Bae M, Patel N, Xu H, Lee M, Tominaga-Yamanaka K, Nath A, Geiger J, Gorospe M, Mattson MP, Haughey NJ. Activation of TRPML1 clears intraneuronal A\u03b2 in preclinical models of HIV infection. J Neurosci. 2014;34(34):11485\u2013503. https:\/\/doi.org\/10.1523\/JNEUROSCI.0210-14.2014.","journal-title":"J Neurosci"},{"issue":"19","key":"3554_CR53","doi-asserted-by":"publisher","first-page":"4709","DOI":"10.1113\/JP275489","volume":"596","author":"HL Christensen","year":"2018","unstructured":"Christensen HL, Barbuskaite D, Rojek A, Malte H, Christensen IB, F\u00fcchtbauer AC, F\u00fcchtbauer E-M, Wang T, Praetorius J, Damkier HH. The choroid plexus sodium-bicarbonate cotransporter NBCe2 regulates mouse cerebrospinal fluid pH. J Physiol. 2018;596(19):4709\u201328. https:\/\/doi.org\/10.1113\/JP275489.","journal-title":"J Physiol"},{"issue":"32","key":"3554_CR54","doi-asserted-by":"publisher","first-page":"12138","DOI":"10.1073\/pnas.0604911103","volume":"103","author":"S Herculano-Houzel","year":"2006","unstructured":"Herculano-Houzel S, Mota B, Lent R. Cellular scaling rules for rodent brains. Proc Natl Acad Sci. 2006;103(32):12138\u201343. https:\/\/doi.org\/10.1073\/pnas.0604911103.","journal-title":"Proc Natl Acad Sci"},{"issue":"1","key":"3554_CR55","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/0165-3806(90)90163-S","volume":"56","author":"RF Keep","year":"1990","unstructured":"Keep RF, Jones HC. A morphometric study on the development of the lateral ventricle choroid plexus choroid plexus capillaries and ventricular ependyma in the rat Developmental. Brain Res. 1990;56(1):47\u201353. https:\/\/doi.org\/10.1016\/0165-3806(90)90163-S.","journal-title":"Brain Res"},{"issue":"3","key":"3554_CR56","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1111\/jnc.12344","volume":"127","author":"GNY Chan","year":"2013","unstructured":"Chan GNY, Saldivia V, Yang Y, Pang H, de Lannoy I, Bendayan R. In vivo induction of P-glycoprotein expression at the mouse blood-brain barrier: an intracerebral microdialysis study. J Neurochem. 2013;127(3):342\u201352. https:\/\/doi.org\/10.1111\/jnc.12344.","journal-title":"J Neurochem"},{"key":"3554_CR57","doi-asserted-by":"publisher","first-page":"11305","DOI":"10.1158\/0008-5472.CAN-06-0929","volume":"66","author":"Y Zhuang","year":"2006","unstructured":"Zhuang Y, Fraga CH, Hubbard KE, Hagedorn N, Panetta JC, Waters CM, Stewart CF. Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor. Cancer Res. 2006;66:11305\u201313. https:\/\/doi.org\/10.1158\/0008-5472.CAN-06-0929.","journal-title":"Cancer Res"},{"key":"3554_CR58","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1007\/s10928-012-9295-8","volume":"40","author":"SF Hudachek","year":"2013","unstructured":"Hudachek SF, Gustafson DL. Physiologically based pharmacokinetic model of lapatinib developed in mice and scaled to humans. J Pharmacokinet Pharmacodyn. 2013;40:157\u201376. https:\/\/doi.org\/10.1007\/s10928-012-9295-8.","journal-title":"J Pharmacokinet Pharmacodyn."},{"key":"3554_CR59","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1007\/s00280-019-03941-z","volume":"84","author":"JH Hughes","year":"2019","unstructured":"Hughes JH, Upton RN, Reuter SE, Rozewski DM, Phelps MA, Foster DJR. Development of a physiologically based pharmacokinetic model for intravenous lenalidomide in mice. Cancer Chemother Pharmacol. 2019;84:1073\u201387. https:\/\/doi.org\/10.1007\/s00280-019-03941-z.","journal-title":"Cancer Chemother Pharmacol."},{"key":"3554_CR60","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1007\/s13318-020-00616-6","volume":"45","author":"J Methaneethorn","year":"2020","unstructured":"Methaneethorn J, Naosang K, Kaewworasut P, Poomsaidorn C, Lohitnavy M. Development of a Physiologically-based pharmacokinetic model of \u03b49-tetrahydrocannabinol in mice, rats, and pigs. Eur J Drug Metab Pharmacokinet. 2020;45:487\u201394. https:\/\/doi.org\/10.1007\/s13318-020-00616-6.","journal-title":"Eur J Drug Metab Pharmacokinet."},{"key":"3554_CR61","doi-asserted-by":"publisher","first-page":"1219","DOI":"10.1007\/s00280-013-2116-y","volume":"71","author":"DK Pawaskar","year":"2013","unstructured":"Pawaskar DK, Straubinger RM, Fetterly GJ, Hylander BH, Repasky EA, Ma WW, Jusko WJ. Physiologically based pharmacokinetic models for everolimus and sorafenib in mice. Cancer Chemother Pharmacol. 2013;71:1219\u201329. https:\/\/doi.org\/10.1007\/s00280-013-2116-y.","journal-title":"Cancer Chemother Pharmacol."},{"key":"3554_CR62","doi-asserted-by":"publisher","unstructured":"Zake DM, Kurlovics J, Zaharenko L, Komasilovs V, Klovins J, Stalidzans E. Physiologically based metformin pharmacokinetics model of mice and scale-up to humans for the estimation of concentrations in various tissues. PLoS One 2021; 16:. https:\/\/doi.org\/10.1371\/journal.pone.0249594.","DOI":"10.1371\/journal.pone.0249594."},{"key":"3554_CR63","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1007\/s11095-022-03281-3","volume":"39","author":"MAA Saleh","year":"2022","unstructured":"Saleh MAA, Bloemberg JS, Elassaiss-Schaap J, de Lange ECM. Drug Distribution in Brain and Cerebrospinal Fluids in Relation to IC50 Values in Aging and Alzheimer\u2019s Disease, Using the Physiologically Based LeiCNS-PK3.0 Model. Pharm Res. 2022;39:1303\u201319. https:\/\/doi.org\/10.1007\/s11095-022-03281-3.","journal-title":"Pharm Res."},{"key":"3554_CR64","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1002\/psp4.12250","volume":"6","author":"Y Yamamoto","year":"2017","unstructured":"Yamamoto Y, V\u00e4litalo PA, Huntjens DR, Proost JH, Vermeulen A, Krauwinkel W, Beukers MW, Van Den Berg DJ, Hartman R, Wong YC, Danhof M, Van Hasselt JGC, De Lange ECM. Predicting drug concentration-time profiles in multiple CNS compartments using a comprehensive physiologically-based pharmacokinetic model. CPT Pharmacomet Syst Pharmacol. 2017;6:765\u201377. https:\/\/doi.org\/10.1002\/psp4.12250.","journal-title":"CPT Pharmacomet Syst Pharmacol."},{"key":"3554_CR65","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1021\/acschemneuro.9b00650","volume":"11","author":"M Gupta","year":"2020","unstructured":"Gupta M, Bogdanowicz T, Reed MA, Barden CJ, Weaver DF. The Brain exposure efficiency (BEE) score. ACS Chem Neurosci. 2020;11:205\u201324. https:\/\/doi.org\/10.1021\/acschemneuro.9b00650.","journal-title":"ACS Chem Neurosci."},{"key":"3554_CR66","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.tiv.2004.06.011","volume":"19","author":"P Garberg","year":"2005","unstructured":"Garberg P, Ball M, Borg N, Cecchelli R, Fenart L, Hurst RD, Lindmark T, Mabondzo A, Nilsson JE, Raub TJ, Stanimirovic D, Terasaki T, \u00d6berg JO, \u00d6sterberg T. In vitro models for the blood-brain barrier. Toxicol Vitr. 2005;19:299\u2013334. https:\/\/doi.org\/10.1016\/j.tiv.2004.06.011.","journal-title":"Toxicol Vitr"},{"key":"3554_CR67","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1007\/s11095-021-03154-1","volume":"39","author":"M Hirasawa","year":"2022","unstructured":"Hirasawa M, Saleh MAA, de Lange ECM. The Extension of the LeiCNS-PK3.0 model in combination with the \u201cHandshake\u201d approach to understand brain tumor pathophysiology. Pharm Res. 2022;39:1343\u201361. https:\/\/doi.org\/10.1007\/s11095-021-03154-1.","journal-title":"Pharm. Res."},{"key":"3554_CR68","doi-asserted-by":"publisher","first-page":"1665","DOI":"10.1021\/acs.jmedchem.6b01483","volume":"60","author":"CR Pye","year":"2017","unstructured":"Pye CR, Hewitt WM, Schwochert J, Haddad TD, Townsend CE, Etienne L, Lao Y, Limberakis C, Furukawa A, Mathiowetz AM, Price DA, Liras S, Lokey RS. Nonclassical Size Dependence of Permeation Defines Bounds for Passive Adsorption of Large Drug Molecules. J Med Chem. 2017;60:1665\u201372. https:\/\/doi.org\/10.1021\/acs.jmedchem.6b01483.","journal-title":"J. Med. Chem."},{"key":"3554_CR69","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/2045-8118-10-12","volume":"10","author":"ECM de Lange","year":"2013","unstructured":"de Lange EC. The mastermind approach to CNS drug therapy: translational prediction of human brain distribution, target site kinetics, and therapeutic effects. Fluids Barriers CNS. 2013;10:12. https:\/\/doi.org\/10.1186\/2045-8118-10-12.","journal-title":"Fluids Barriers CNS"},{"key":"3554_CR70","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1002\/cpt.2545","volume":"111","author":"ECM de Lange","year":"2022","unstructured":"de Lange ECM, Hammarlund Udenaes M. Understanding the blood-brain barrier and beyond: challenges and opportunities for novel cns therapeutics. Clin Pharmacol Ther. 2022;111:758\u201373. https:\/\/doi.org\/10.1002\/cpt.2545.","journal-title":"Clin Pharmacol Ther."}],"container-title":["Pharmaceutical Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11095-023-03554-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11095-023-03554-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11095-023-03554-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,20]],"date-time":"2023-12-20T16:06:46Z","timestamp":1703088406000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11095-023-03554-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,13]]},"references-count":70,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2023,11]]}},"alternative-id":["3554"],"URL":"https:\/\/doi.org\/10.1007\/s11095-023-03554-5","relation":{},"ISSN":["0724-8741","1573-904X"],"issn-type":[{"value":"0724-8741","type":"print"},{"value":"1573-904X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,13]]},"assertion":[{"value":"16 May 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 June 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 July 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}}]}}