PURPOSE: To examine functional activity of P-glycoprotein (P-gp) in the blood-brain barrier (BBB) using near infrared fluorescence (NIRF) imaging techniques. METHODS: Cellular accumulation and bi-directional permeability of the NIRF probe, rhodamine 800 (R800) was determined in MDCKMDR1 and MDCKwt monolayers under normal conditions and following P-gp inhibition with GF120918. Functional P-gp activity was also assessed in mice following administration of R800 alone and with GF230918. Quantitative analysis of R800 fluorescence in brain tissue and blood was measured ex-vivo using Odyssey Near Infrared imaging. RESULTS: R800 accumulation was reduced in MDCKMDR1 compared to MDCKwt monolayers. Addition of GF120918, resulted in increased R800 accumulation in MDCKMDR1 monolayers. Permeability of R800 in MDCKMDR1 monolayers was significantly enhanced (4-fold) in the basolateral to apical direction under control conditions and was abolished following treatment with GF120918. With the exception of the choriod plexus, there was very little penetration of R800 into the brain under control conditions. Treatment of mice with GF120918 resulted in a nearly 4-fold increase in R800 fluorescence in the brain. In contrast, GF120918 had no effect on brain penetration of a vascular permeability marker. CONCLUSIONS: In vitro studies demonstrate the P-gp transporter properties of the NIRF probe R800. Preliminary in vivo studies confirm the P-gp transporter liabilities of R800 and suggest this probe may be useful as a molecular imaging agent for examining P-gp activity in the BBB.
PURPOSE: To examine functional activity of P-glycoprotein (P-gp) in the blood-brain barrier (BBB) using near infrared fluorescence (NIRF) imaging techniques. METHODS: Cellular accumulation and bi-directional permeability of the NIRF probe, rhodamine 800 (R800) was determined in MDCKMDR1 and MDCKwt monolayers under normal conditions and following P-gp inhibition with GF120918. Functional P-gp activity was also assessed in mice following administration of R800 alone and with GF230918. Quantitative analysis of R800 fluorescence in brain tissue and blood was measured ex-vivo using Odyssey Near Infrared imaging. RESULTS: R800 accumulation was reduced in MDCKMDR1 compared to MDCKwt monolayers. Addition of GF120918, resulted in increased R800 accumulation in MDCKMDR1 monolayers. Permeability of R800 in MDCKMDR1 monolayers was significantly enhanced (4-fold) in the basolateral to apical direction under control conditions and was abolished following treatment with GF120918. With the exception of the choriod plexus, there was very little penetration of R800 into the brain under control conditions. Treatment of mice with GF120918 resulted in a nearly 4-fold increase in R800 fluorescence in the brain. In contrast, GF120918 had no effect on brain penetration of a vascular permeability marker. CONCLUSIONS: In vitro studies demonstrate the P-gp transporter properties of the NIRF probe R800. Preliminary in vivo studies confirm the P-gp transporter liabilities of R800 and suggest this probe may be useful as a molecular imaging agent for examining P-gp activity in the BBB.
Authors: Kathleen M Giacomini; Shiew-Mei Huang; Donald J Tweedie; Leslie Z Benet; Kim L R Brouwer; Xiaoyan Chu; Amber Dahlin; Raymond Evers; Volker Fischer; Kathleen M Hillgren; Keith A Hoffmaster; Toshihisa Ishikawa; Dietrich Keppler; Richard B Kim; Caroline A Lee; Mikko Niemi; Joseph W Polli; Yuichi Sugiyama; Peter W Swaan; Joseph A Ware; Stephen H Wright; Sook Wah Yee; Maciej J Zamek-Gliszczynski; Lei Zhang Journal: Nat Rev Drug Discov Date: 2010-03 Impact factor: 84.694
Authors: M Horio; K V Chin; S J Currier; S Goldenberg; C Williams; I Pastan; M M Gottesman; J Handler Journal: J Biol Chem Date: 1989-09-05 Impact factor: 5.157
Authors: J W Jonker; E Wagenaar; L van Deemter; R Gottschlich; H M Bender; J Dasenbrock; A H Schinkel Journal: Br J Pharmacol Date: 1999-05 Impact factor: 8.739
Authors: S M Dombrowski; S Y Desai; M Marroni; L Cucullo; K Goodrich; W Bingaman; M R Mayberg; L Bengez; D Janigro Journal: Epilepsia Date: 2001-12 Impact factor: 5.864
Authors: Kazuto Yasuda; Cynthia Cline; Peter Vogel; Mihaela Onciu; Soghra Fatima; Brian P Sorrentino; Ranjit K Thirumaran; Sean Ekins; Yoshihiro Urade; Ko Fujimori; Erin G Schuetz Journal: Drug Metab Dispos Date: 2013-01-08 Impact factor: 3.922
Authors: Ahmed Alaofi; Ngoc On; Paul Kiptoo; Todd D Williams; Donald W Miller; Teruna J Siahaan Journal: J Pharm Sci Date: 2016-02 Impact factor: 3.534
Authors: Inessa Semenenko; Emma Portnoy; Mohammed Aboukaoud; Serge Guzy; Miriam Shmuel; Gal Itzhak; Sara Eyal Journal: Front Pharmacol Date: 2016-11-15 Impact factor: 5.810
Authors: Zhizhi Sun; Matthew Worden; Yaroslav Wroczynskyj; Vinith Yathindranath; Johan van Lierop; Torsten Hegmann; Donald W Miller Journal: Int J Nanomedicine Date: 2014-06-20