{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T05:14:21Z","timestamp":1738300461012,"version":"3.35.0"},"reference-count":33,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2009,1,29]],"date-time":"2009-01-29T00:00:00Z","timestamp":1233187200000},"content-version":"vor","delay-in-days":212,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2008,7]]},"abstract":"<jats:sec><jats:title>Background and purpose:<\/jats:title><jats:p>The pharmacokinetic\u2013pharmacodynamic (PK\u2013PD) correlation of fluvoxamine 5\u2010HT transporter (SERT) occupancy was determined in rat frontal cortex<jats:italic>ex vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental approach:<\/jats:title><jats:p>Rats (<jats:italic>n<\/jats:italic>=47) with permanent arterial and venous cannulas received a 30\u2003min intravenous infusion of fluvoxamine (1 or 7.3\u2003mg\u2003kg<jats:sup>\u22121<\/jats:sup>). At various time points after dosing, brains were collected for determination of fluvoxamine concentration and SERT occupancy. In addition, the time course of fluvoxamine concentration in plasma was determined up to the time of brain collection. In a separate study (<jats:italic>n<\/jats:italic>=26), the time course of fluvoxamine concentration in brain extracellular fluid (ECF) and plasma was determined. The results of the investigations were interpreted by nonlinear mixed effects modeling<\/jats:p><\/jats:sec><jats:sec><jats:title>Key results:<\/jats:title><jats:p>Highest SERT occupancy was reached at the first time point (10 or 15\u2003min) and maintained for 1.5 and 7\u2003h after 1 and 7.3\u2003mg\u2003kg<jats:sup>\u22121<\/jats:sup>, respectively. Thereafter, SERT occupancy decreased linearly at a rate of 8%\u2003h<jats:sup>\u22121<\/jats:sup>. SERT occupancy could be directly related to plasma, brain ECF and brain tissue concentrations by a hyperbolic function (<jats:italic>B<\/jats:italic><jats:sub>max<\/jats:sub>model). Maximal SERT occupancy (<jats:italic>B<\/jats:italic><jats:sub>max<\/jats:sub>) was 95%. Estimated concentrations at half\u2010maximal SERT occupancy (EC<jats:sub>50<\/jats:sub>) in plasma, ECF and brain tissue were 0.48, 0.22 and 14.8\u2003ng\u2003mL<jats:sup>\u22121<\/jats:sup>respectively. The minimum value of the objective function decreased 12 points for ECF and brain tissue concentrations relative to plasma (<jats:italic>P<\/jats:italic>&lt;0.01), presumably as a result of nonlinear brain distribution.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and implications:<\/jats:title><jats:p>The proposed PK\u2013PD model constitutes a useful basis for prediction of the time course of<jats:italic>ex vivo<\/jats:italic>SERT occupancy in behavioural studies with selective serotonin reuptake inhibitors.<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic>(2008)<jats:bold>154<\/jats:bold>, 1369\u20131378; doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/bjp.2008.179\">10.1038\/bjp.2008.179<\/jats:ext-link>; published online 19 May 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