{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T15:19:33Z","timestamp":1760887173400,"version":"3.28.0"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2000,3,1]],"date-time":"2000-03-01T00:00:00Z","timestamp":951868800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2000,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>This study was designed to test the hypothesis that lipophilic cationic drugs with only roughly similar structures mediate the reversal of multidrug-resistance (MDR) by interacting with membrane phospholipids. The permeation properties of MDR-modulators and non-modulators were studied by quantifying their ability to induce the leakage of Sulphan blue through the membrane of negatively charged unilamellar liposomes.<\/jats:p>\n               <jats:p>Of the 22 compounds under investigation, only those bearing a net positive electric charge per molecule (z) \u22650.2 induced dye leakage. All these efficient drugs are well-known MDR-modulators: calcium-channel blockers (propranolol, verapamil, diltiazem and dipyridamole), calmodulin antagonists (clomipramine and thioridazine) and antiparasitic agents (mepacrine, thioacridine derivatives and quinine). The non-modulators tested, including antineoplasic agents and steroids, did not induce any membrane permeation. The permeation process was a co-operative one (1.1 &amp;lt; Hill coefficient &amp;lt; 4.1) and the permeation doses inducing 50% dye leakage (PD50) were 1.9\u201311.2 mm. The permeation ability of the MDR-modulators (log(1\/PD50)) increased significantly with octanol-buffer distributions per unit net electric charge ((logD)\/z).<\/jats:p>\n               <jats:p>The results provide evidence that a complex interplay occurs between the electric charge and the lipophilicity of the MDR-modulators when a dye leakage is induced through model membranes, and probably also when the MDR is reversed in leukaemic cells.<\/jats:p>","DOI":"10.1211\/0022357001773977","type":"journal-article","created":{"date-parts":[[2002,10,1]],"date-time":"2002-10-01T22:04:05Z","timestamp":1033509845000},"page":"289-296","source":"Crossref","is-referenced-by-count":28,"title":["Membrane Permeation by Multidrug-resistance-modulators and Non-modulators: Effects of Hydrophobicity and Electric Charge"],"prefix":"10.1093","volume":"52","author":[{"given":"Madeleine","family":"Castaing","sequence":"first","affiliation":[{"name":"GERCTOP-ESA6009, Facult\u00e9 de Pharmacie , Marseille, Paris,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pierre","family":"Brouant","sequence":"additional","affiliation":[{"name":"GERCTOP-ESA6009, Facult\u00e9 de Pharmacie , Marseille, Paris,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alain","family":"Loiseau","sequence":"additional","affiliation":[{"name":"INSERM-IFR2, Facult\u00e9 de M\u00e9decine Xavier-Bichat , Paris,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christiane","family":"Santelli-Rouvier","sequence":"additional","affiliation":[{"name":"GERCTOP-ESA6009, Facult\u00e9 de Pharmacie , Marseille, Paris,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maurice","family":"Santelli","sequence":"additional","affiliation":[{"name":"Laboratoire de Synth\u00e8se Organique ESA6009, Facult\u00e9 des Sciences de St-J\u00e9r\u00f4me , Marseille,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandrine","family":"Alibert-Franco","sequence":"additional","affiliation":[{"name":"GERCTOP-ESA6009, Facult\u00e9 de Pharmacie , Marseille, Paris,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdallah","family":"Mahamoud","sequence":"additional","affiliation":[{"name":"GERCTOP-ESA6009, Facult\u00e9 de Pharmacie , Marseille, Paris,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacques","family":"Barbe","sequence":"additional","affiliation":[{"name":"GERCTOP-ESA6009, Facult\u00e9 de Pharmacie , Marseille, Paris,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2000,3,1]]},"reference":[{"key":"2024103110044188700_cit1","doi-asserted-by":"crossref","first-page":"2879","DOI":"10.1016\/0006-2952(87)90198-5","article-title":"The cell biology of multiple drug resistance","volume":"36","author":"Beck","year":"1987","journal-title":"Biochem. 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Chem."},{"key":"2024103110044188700_cit9","first-page":"237","article-title":"Drug compendium","volume-title":"Comprehensive Medicinal Chemistry","author":"Craig","year":"1990"},{"key":"2024103110044188700_cit10","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1111\/j.1432-1033.1995.tb20352.x","article-title":"Potentiation of anticancer-drug cytotoxicity by multidrug-resistance chemosensitizers involves alterations in membrane fluidity leading to increased membrane permeability","volume":"228","author":"Drori","year":"1995","journal-title":"Eur. J. Biochem."},{"key":"2024103110044188700_cit11","doi-asserted-by":"crossref","first-page":"4767","DOI":"10.1021\/jm960384x","article-title":"Structure-activity relationship studies on benzofuran analogs of propafenone-type modulators of tumor cell multidrug resistance","volume":"39","author":"Ecker","year":"1996","journal-title":"J. Med. 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