{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T01:23:18Z","timestamp":1792027398177,"version":"4.4.0"},"reference-count":52,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2011,7,11]],"date-time":"2011-07-11T00:00:00Z","timestamp":1310342400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2011,8]]},"abstract":"<jats:p><jats:bold>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT<\/jats:bold><\/jats:p><jats:p>\u2022\u2003This study provides antimuscarinic agents for overactive bladder (OAB) display variable association with side effects mediated by the central nervous system (CNS), which may be of particular concern in the elderly.<\/jats:p><jats:p>\u2022\u2003Adverse effects on CNS functioning are related to muscarinic receptor subtype selectivity and the ability of the agent to cross the blood\u2212brain barrier, where P\u2010gp plays a role in limiting permeability.<\/jats:p><jats:p><jats:bold>WHAT THIS STUDY ADDS<\/jats:bold><\/jats:p><jats:p>\u2022\u2003This study provides a parallel investigation of CNS penetration of antimuscarinic OAB agents<jats:italic>in vivo<\/jats:italic>and assessment of physical properties and permeability in cell monolayers<jats:italic>in vitro<\/jats:italic>.<\/jats:p><jats:p>\u2022\u2003It adds further understanding of the roles of passive transcellular permeability and P\u2010gp in determining CNS penetration of antimuscarinic OAB agents.<\/jats:p><jats:p>\u2022\u2003It also enables a comparison of CNS side\u2010effect profiles of OAB agents with preclinical CNS penetration data.<\/jats:p><jats:p><jats:bold>AIMS<\/jats:bold>To assess and compare the mechanisms of central nervous system (CNS) penetration of antimuscarinic overactive bladder (OAB) agents.<\/jats:p><jats:p><jats:bold>METHODS<\/jats:bold>Physical properties were computed or compiled from the literature. Rats were administered 5\u2010hydroxymethyl tolterodine (HMT), darifenacin, oxybutynin, solifenacin, tolterodine or trospium subcutaneously. At 1\u2003h postdose, plasma, brain and cerebrospinal fluid (CSF) concentrations were determined using LC\u2010MS\/MS assays. Brain and plasma protein binding were determined<jats:italic>in vitro<\/jats:italic>. Permeability in the presence and absence of the efflux transporter P\u2010glycoprotein (P\u2010gp) was assessed in RRCK and MDCK\u2010MDR1 transwell assays.<\/jats:p><jats:p><jats:bold>RESULTS<\/jats:bold>Oxybutynin displayed extensive CNS penetration, with brain\u2003:\u2003plasma ratios (B\u2003:\u2003P), unbound brain\u2003:\u2003unbound plasma ratios (Kp,free) and CSF\u2003:\u2003free plasma ratios each &gt;1. Tolterodine (B\u2003:\u2003P = 2.95, Kp,free = 0.23 and CSF\u2003:\u2003free plasma = 0.16) and solifenacin (B\u2003:\u2003P = 3.04, Kp,free = 0.28 and CSF\u2003:\u2003free plasma = 1.41) showed significant CNS penetration but with some restriction from CNS as indicated by Kp,free values significantly &lt;1. 5\u2010HMT, darifenacin and trospium displayed much lower B\u2003:\u2003P (0.03\u20130.16), Kp,free (0.01\u20130.04) and CSF\u2003:\u2003free plasma (0.004\u20130.06), consistent with poor CNS penetration. Permeability in RRCK cells was low for trospium (0.63 \u00d7 10<jats:sup>\u22126<\/jats:sup>\u2003cm\u2003s<jats:sup>\u22121<\/jats:sup>), moderate for 5\u2010HMT (11.7 \u00d7 10<jats:sup>\u22126<\/jats:sup>\u2003cm\u2003s<jats:sup>\u22121<\/jats:sup>) and high for darifenacin, solifenacin, tolterodine and oxybutynin (21.5\u201338.2 \u00d7 10<jats:sup>\u22126<\/jats:sup>\u2003cm\u2003s<jats:sup>\u22121<\/jats:sup>). In MDCK\u2010MDR1 cells 5\u2010HMT, darifenacin and trospium, were P\u2010gp substrates, whereas oxybutynin, solifenacin and tolterodine were not P\u2010gp substrates.<\/jats:p><jats:p><jats:bold>CONCLUSIONS<\/jats:bold>Brain penetration was low for antimuscarinics that are P\u2010gp substrates (5\u2010HMT, darifenacin and trospium), and significant for those that are not P\u2010gp substrates (oxybutynin, solifenacin and tolterodine). CNS adverse events reported in randomized controlled clinical trials show general alignment with the preclinical data described in this study.<\/jats:p>","DOI":"10.1111\/j.1365-2125.2011.03961.x","type":"journal-article","created":{"date-parts":[[2011,3,11]],"date-time":"2011-03-11T10:34:44Z","timestamp":1299839684000},"page":"235-246","source":"Crossref","is-referenced-by-count":165,"title":["A comprehensive non\u2010clinical evaluation of the CNS penetration potential of antimuscarinic agents for the treatment of overactive bladder"],"prefix":"10.1111","volume":"72","author":[{"given":"Ernesto","family":"Callegari","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bimal","family":"Malhotra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Bungay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob","family":"Webster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine S.","family":"Fenner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Kempshall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer L.","family":"LaPerle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin C.","family":"Michel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary G.","family":"Kay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2011,7,11]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/nau.20798"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1520-6777(2000)19:3<259::AID-NAU7>3.0.CO;2-U"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1464-410x.2001.02228.x"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2009.05.028"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0090-4295(02)01788-0"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2005.02.024"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2008.06.047"},{"key":"e_1_2_6_9_2","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/S0031-6997(24)01362-0","article-title":"International Union of Pharmacology. 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