{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T10:24:55Z","timestamp":1781778295077,"version":"3.54.5"},"reference-count":46,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2023,8,1]],"date-time":"2023-08-01T00:00:00Z","timestamp":1690848000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2023,8,1]],"date-time":"2023-08-01T00:00:00Z","timestamp":1690848000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2023,5,26]],"date-time":"2023-05-26T00:00:00Z","timestamp":1685059200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007601","name":"Horizon 2020","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007601","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018693","name":"Horizon 2020","doi-asserted-by":"publisher","award":["848068"],"award-info":[{"award-number":["848068"]}],"id":[{"id":"10.13039\/100018693","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Pharmaceutical Sciences"],"published-print":{"date-parts":[[2023,8]]},"DOI":"10.1016\/j.ejps.2023.106482","type":"journal-article","created":{"date-parts":[[2023,5,27]],"date-time":"2023-05-27T15:11:51Z","timestamp":1685200311000},"page":"106482","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":4,"special_numbering":"C","title":["Does nonlinear blood-brain barrier transport matter for (lower) morphine dosing strategies?"],"prefix":"10.1016","volume":"187","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8954-882X","authenticated-orcid":false,"given":"Berfin","family":"G\u00fclave","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divakar","family":"Budda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed AA","family":"Saleh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JG Coen","family":"van Hasselt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8303-1117","authenticated-orcid":false,"given":"Elizabeth CM","family":"de Lange","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.ejps.2023.106482_bib0001","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1021\/acs.molpharmaceut.8b01189","article-title":"Proteomic quantification of human blood-brain barrier SLC and ABC transporters in healthy individuals and dementia patients","volume":"16","author":"Al-Majdoub","year":"2019","journal-title":"Mol. Pharm."},{"key":"10.1016\/j.ejps.2023.106482_bib0002","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1111\/jnc.14446","article-title":"Identification and quantification of blood\u2013brain barrier transporters in isolated rat brain microvessels","volume":"146","author":"Al Feteisi","year":"2018","journal-title":"J. Neurochem."},{"key":"10.1016\/j.ejps.2023.106482_bib0003","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1046\/j.1471-4159.2003.01990.x","article-title":"Evidence for an active transport of morphine-6-\u03b2-D-glucuronide but not P-glycoprotein-mediated at the blood-brain barrier","volume":"86","author":"Bourasset","year":"2003","journal-title":"J. Neurochem."},{"key":"10.1016\/j.ejps.2023.106482_bib0004","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1038\/sj.bjp.0704406","article-title":"Blood-brain barrier transport and brain distribution of morphine-6-glucuronide in relation to the antinociceptive effect in rats - Pharmacokinetic\/pharmacodynamic modelling","volume":"134","author":"Bouw","year":"2001","journal-title":"Br. J. Pharmacol."},{"key":"10.1016\/j.ejps.2023.106482_bib0005","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.2174\/1570159X15666170504095823","article-title":"Opioids and the blood-brain barrier: a dynamic interaction with consequences on drug disposition in brain","volume":"15","author":"Chaves","year":"2017","journal-title":"Curr. Neuropharmacol."},{"key":"10.1016\/j.ejps.2023.106482_bib0006","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1111\/j.1399-6576.1997.tb04625.x","article-title":"Morphine metabolites","volume":"41","author":"Christrup","year":"1997","journal-title":"Acta Anaesthesiol. Scand."},{"key":"10.1016\/j.ejps.2023.106482_bib0007","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11011-011-9274-6","article-title":"Morphine metabolism, transport and Brain disposition","volume":"27","author":"De Gregori","year":"2012","journal-title":"Metab. Brain Dis."},{"key":"10.1016\/j.ejps.2023.106482_bib0008","unstructured":"FDA, 2012. Morphine sulphate tablets FDA label. Ref. ID 3075779."},{"key":"10.1016\/j.ejps.2023.106482_bib0009","unstructured":"FDA, 1984. Morphine sulfate injection FDA label."},{"key":"10.1016\/j.ejps.2023.106482_bib0010","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1016\/j.bcp.2011.03.001","article-title":"Distinct pharmacological properties of morphine metabolites at G i-protein and \u03b2-arrestin signaling pathways activated by the human \u03bc-opioid receptor","volume":"81","author":"Fr\u00f6lich","year":"2011","journal-title":"Biochem. Pharmacol."},{"key":"10.1016\/j.ejps.2023.106482_bib0011","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fnmol.2022.882443","article-title":"Morphine-3-Glucuronide, Physiology and Behavior","volume":"15","author":"Gabel","year":"2022","journal-title":"Front. Mol. Neurosci."},{"key":"10.1016\/j.ejps.2023.106482_bib0012","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/sj.bjp.0707257","article-title":"Population pharmacokinetic modelling of non-linear brain distribution of morphine: influence of active saturable influx and P-glycoprotein mediated efflux","volume":"151","author":"Groenendaal","year":"2007","journal-title":"Br. J. Pharmacol."},{"key":"10.1016\/j.ejps.2023.106482_bib0013","doi-asserted-by":"crossref","first-page":"3343","DOI":"10.1002\/jps.23575","article-title":"Quantitative atlas of blood\u2013brain barrier transporters, receptors, and tight junction proteins in rats and common marmoset","volume":"102","author":"Hoshi","year":"2013","journal-title":"J. Pharm. Sci."},{"key":"10.1016\/j.ejps.2023.106482_bib0014","doi-asserted-by":"crossref","unstructured":"Imming, P., Sinning, C., Meyer, A., 2007. Drugs, their targets and the nature and number of drug targets 5, 821\u2013835.","DOI":"10.1038\/nrd2132"},{"key":"10.1016\/j.ejps.2023.106482_bib0015","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1093\/bja\/aeu186","article-title":"Morphine-6-glucuronide is responsible for the analgesic effect after morphine administration: a quantitative review of morphine, morphine-6-glucuronide, and morphine-3-glucuronide","volume":"113","author":"Klimas","year":"2014","journal-title":"Br. J. Anaesth."},{"key":"10.1016\/j.ejps.2023.106482_bib0016","doi-asserted-by":"crossref","first-page":"PL45","DOI":"10.1016\/0024-3205(94)00937-6","article-title":"The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine","volume":"56","author":"Kristensen","year":"1995","journal-title":"Life Sci."},{"key":"10.1016\/j.ejps.2023.106482_bib0017","first-page":"827","article-title":"Effects of a potent and specific P-glycoprotein inhibitor on the blood- brain barrier distribution and antinoclceptive effect of morphine in the rat","volume":"27","author":"Letrent","year":"1999","journal-title":"Drug Metab. Dispos."},{"key":"10.1016\/j.ejps.2023.106482_bib0018","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1046\/j.1471-4159.2002.01177.x","article-title":"Increased CNS uptake and enhanced antinociception of morphine-6-glucuronide in rats after inhibition of P-glycoprotein","volume":"83","author":"L\u00f6tsch","year":"2002","journal-title":"J. Neurochem."},{"key":"10.1016\/j.ejps.2023.106482_bib0019","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1067\/mcp.2002.126172","article-title":"Pharmacokinetic modeling to predict morphine and morphinc-6-glucuronide plasma concentrations in healthy young volunteers","volume":"72","author":"L\u00f6tsch","year":"2002","journal-title":"Clin. Pharmacol. Ther."},{"key":"10.1016\/j.ejps.2023.106482_bib0020","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1177\/00912700222011508","article-title":"Contribution of morphine-6-glucuronide to antinociception following intravenous administration of morphine to healthy volunteers","volume":"42","author":"Murthy","year":"2002","journal-title":"J. Clin. Pharmacol."},{"key":"10.1016\/j.ejps.2023.106482_bib0021","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1124\/dmd.108.022087","article-title":"Involvement of the pyrilamine transporter, a putative organic cation transporter, in blood-brain barrier transport of oxycodone","volume":"36","author":"Okura","year":"2008","journal-title":"Drug Metab. Dispos."},{"key":"10.1016\/j.ejps.2023.106482_bib0022","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1007\/s40262-016-0471-7","article-title":"A prospective population pharmacokinetic study on morphine metabolism in cancer patients","volume":"56","author":"Oosten","year":"2017","journal-title":"Clin. Pharmacokinet."},{"key":"10.1016\/j.ejps.2023.106482_bib0023","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.drugalcdep.2012.01.013","article-title":"Opioid receptor expression in human brain and peripheral tissues using absolute quantitative real-time RT-PCR","volume":"124","author":"Peng","year":"2012","journal-title":"Drug Alcohol Depend."},{"key":"10.1016\/j.ejps.2023.106482_bib0024","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/S0959-4388(02)00313-6","article-title":"Brain mechanisms of pain affect and pain modulation","volume":"12","author":"Rainville","year":"2002","journal-title":"Curr. Opin. Neurobiol."},{"key":"10.1016\/j.ejps.2023.106482_bib0025","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1007\/s10928-021-09768-7","article-title":"Lumbar cerebrospinal fluid-to-brain extracellular fluid surrogacy is context-specific: insights from LeiCNS-PK3.0 simulations","volume":"48","author":"Saleh","year":"2021","journal-title":"J. Pharmacokinet. Pharmacodyn."},{"key":"10.1016\/j.ejps.2023.106482_bib0026","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1021\/mp200129p","article-title":"Transcriptomic and quantitative proteomic analysis of transporters and drug metabolizing enzymes in freshly isolated human brain microvessels","volume":"8","author":"Shawahna","year":"2011","journal-title":"Mol. Pharm."},{"key":"10.1016\/j.ejps.2023.106482_bib0027","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1097\/00000542-200412000-00020","article-title":"Probenecid interacts with the pharmacokinetics of morphine-6-glucuromide in humans","volume":"101","author":"Skarke","year":"2004","journal-title":"Anesthesiology"},{"key":"10.1016\/j.ejps.2023.106482_bib0028","first-page":"316","article-title":"Characterization of the efflux transport of 17\u03b2-estradiol-D-17\u03b2-glucuronide from the brain across the blood-brain barrier","volume":"298","author":"Sugiyama","year":"2001","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"10.1016\/j.ejps.2023.106482_bib0029","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.neuropharm.2013.08.019","article-title":"In vitro morphine metabolism by rat microglia","volume":"75","author":"Togna","year":"2013","journal-title":"Neuropharmacology"},{"key":"10.1016\/j.ejps.2023.106482_bib0030","series-title":"Essentials of Pharmacokinetics and Pharmacodynamics","author":"Tozer","year":"2016"},{"key":"10.1016\/j.ejps.2023.106482_bib0031","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.ejps.2004.09.009","article-title":"Influence of probenecid on the delivery of morphine-6-glucuronide to the brain","volume":"24","author":"Tunblad","year":"2005","journal-title":"Eur. J. Pharm. Sci."},{"key":"10.1016\/j.ejps.2023.106482_bib0032","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1023\/A:1023250900462","article-title":"Morphine blood-brain barrier transport is influenced by probenecid co-administration","volume":"20","author":"Tunblad","year":"2003","journal-title":"Pharm. Res."},{"key":"10.1016\/j.ejps.2023.106482_bib0033","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1016\/j.bcp.2013.06.019","article-title":"Morphine is a substrate of the organic cation transporter OCT1 and polymorphisms in OCT1 gene affect morphine pharmacokinetics after codeine administration","volume":"86","author":"Tzvetkov","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"10.1016\/j.ejps.2023.106482_bib0034","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1111\/j.1471-4159.2011.07208.x","article-title":"Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors","volume":"117","author":"Uchida","year":"2011","journal-title":"J. Neurochem."},{"key":"10.1016\/j.ejps.2023.106482_bib0035","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1080\/00498250701546012","article-title":"Functional involvement of organic cation transporter1 (OCT1\/Oct1) in the hepatic uptake of organic cations in humans and rats","volume":"37","author":"Umehara","year":"2007","journal-title":"Xenobiotica"},{"key":"10.1016\/j.ejps.2023.106482_bib0036","first-page":"278","article-title":"Essential medicines: paediatric morphine dosage","volume":"26","year":"2012","journal-title":"WHO Drug Inf."},{"key":"10.1016\/j.ejps.2023.106482_bib0037","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1097\/AJP.0b013e3181c49e3a","article-title":"Delta and kappa opioid receptors as suitable drug targets for pain","volume":"26","author":"Vanderah","year":"2010","journal-title":"Clin. J. Pain"},{"key":"10.1016\/j.ejps.2023.106482_bib0038","doi-asserted-by":"crossref","first-page":"D1074","DOI":"10.1093\/nar\/gkx1037","article-title":"DrugBank 5.0: a major update to the DrugBank database for 2018","volume":"46","author":"Wishart","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.ejps.2023.106482_bib0039","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1111\/j.1365-2125.2011.03925.x","article-title":"Understanding the time course of pharmacological effect: a PKPD approach","volume":"71","author":"Wright","year":"2011","journal-title":"Br. J. Clin. Pharmacol."},{"key":"10.1016\/j.ejps.2023.106482_bib0040","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1038\/sj.bjp.0703759","article-title":"Modelling of the blood-brain barrier transport of morphine-3-glucuronide studied using microdialysis in the rat: involvement of probenecid-sensitive transport","volume":"131","author":"Xie","year":"2000","journal-title":"Br. J. Pharmacol."},{"key":"10.1016\/j.ejps.2023.106482_bib0041","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/sj.bjp.0702804","article-title":"The role of P-glycoprotein in blood-brain barrier transport of morphine: transcortical microdialysis studies in mdr1a (-\/-)and mdr1a (+\/+) mice","volume":"128","author":"Xie","year":"1999","journal-title":"Br. J. Pharmacol."},{"key":"10.1016\/j.ejps.2023.106482_bib0042","doi-asserted-by":"crossref","first-page":"395","DOI":"10.2131\/jts.28.395","article-title":"Formation of highly analgesic morphine-6-glucuronide following physiologic concentration of morphine in human brain","volume":"28","author":"Yamada","year":"2003","journal-title":"J. Toxicol. Sci."},{"key":"10.1016\/j.ejps.2023.106482_bib0043","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.brainres.2006.01.095","article-title":"Morphine can produce analgesia via spinal kappa opioid receptors in the absence of mu opioid receptors","volume":"1083","author":"Yamada","year":"2006","journal-title":"Brain Res."},{"key":"10.1016\/j.ejps.2023.106482_bib0044","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1002\/psp4.12250","article-title":"Predicting drug concentration-time profiles in multiple CNS compartments using a comprehensive physiologically-based pharmacokinetic model","volume":"6","author":"Yamamoto","year":"2017","journal-title":"CPT Pharmacomet. Syst. Pharmacol."},{"key":"10.1016\/j.ejps.2023.106482_bib0045","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1007\/s11095-016-2065-3","article-title":"A generic multi-compartmental CNS distribution model structure for 9 drugs allows prediction of human brain target site concentrations","volume":"34","author":"Yamamoto","year":"2017","journal-title":"Pharm. Res."},{"key":"10.1016\/j.ejps.2023.106482_bib0046","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.ejps.2017.11.011","article-title":"Prediction of human CNS pharmacokinetics using a physiologically-based pharmacokinetic modeling approach","volume":"112","author":"Yamamoto","year":"2018","journal-title":"Eur. J. Pharm. Sci."}],"updated-by":[{"DOI":"10.1016\/j.ejps.2024.106736","type":"erratum","label":"Erratum","source":"publisher","updated":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T00:00:00Z","timestamp":1714521600000}}],"container-title":["European Journal of Pharmaceutical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0928098723001124?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0928098723001124?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2024,4,27]],"date-time":"2024-04-27T05:59:41Z","timestamp":1714197581000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0928098723001124"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8]]},"references-count":46,"alternative-id":["S0928098723001124"],"URL":"https:\/\/doi.org\/10.1016\/j.ejps.2023.106482","relation":{"erratum":[{"id-type":"doi","id":"10.1016\/j.ejps.2024.106736","asserted-by":"object"}]},"ISSN":["0928-0987"],"issn-type":[{"value":"0928-0987","type":"print"}],"subject":[],"published":{"date-parts":[[2023,8]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Does nonlinear blood-brain barrier transport matter for (lower) morphine dosing strategies?","name":"articletitle","label":"Article Title"},{"value":"European Journal of Pharmaceutical Sciences","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ejps.2023.106482","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2023 The Authors. Published by Elsevier B.V.","name":"copyright","label":"Copyright"}],"article-number":"106482"}}