title: Effect of the ABCB1 modulators elacridar and tariquidar on the distribution of paclitaxel in nude mice.
abstract: OBJECTIVE
  Previously, we studied the effect of co-administration of paclitaxel with the second generation ABCB1 (p-gp) modulator valspodar on the intracerebral growth of human U118-MG glioblastoma in nude mice. Valspodar significantly increased the brain levels of paclitaxel by inhibition of p-gp expressed at the blood brain barrier. Thus, the tumour burden was reduced by 90%, which was considered as a proof of concept. However, the paclitaxel dose had to be reduced because of toxic side effects resulting from increased drug levels due to p-gp modulation in peripheral tissues. Therefore, in the present study we examined the co-application of paclitaxel with the third generation ABCB1 modulators elacridar and tariquidar, which were supposed to preferentially modulate p-gp in brain capillaries.
  
  
  METHODS
  The inhibitory activity of the modulators was measured by a flow cytometric and a chemosensitivity assay in vitro. To determine the distribution of paclitaxel in vivo, nude mice received 50 mg/kg of valspodar, elacridar or tariquidar p.o. (control: vehicle) 4 h before i.v. injection of 8 mg/kg of paclitaxel. Brain, liver, kidney and plasma were collected and analyzed by RP-HPLC.
  
  
  RESULTS
  Our in vitro experiments demonstrate that the new modulators are about 80 times more effective in comparison to valspodar. Co-administration of paclitaxel with elacridar and tariquidar led to a long lasting fivefold increase in the concentration of the cytostatic in the brain. Although the increase (2.5- to 7-fold) tended to be lower compared to that induced by co-administered valspodar (six- to eightfold), the brain/plasma ratios achieved with the new modulators were 2-15 times higher.
  
  
  CONCLUSIONS
  Elacridar and tariquidar seem to modulate p-glycoprotein preferentially at the blood-brain barrier. Our results suggest that the systemic toxicity of cytostatics combined with elacridar or tariquidar should be lower than in combination with valspodar.
authors.affiliation: Institute of Pharmacy, University of Regensburg, Universitätsstrasse 31, 93040 Regensburg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Hubensack
authors.forename: Christine
authors.initials: C
authors.lastname: Müller
authors.forename: Peter
authors.initials: P
authors.lastname: Höcherl
authors.forename: Stephan
authors.initials: S
authors.lastname: Fellner
authors.forename: Thilo
authors.initials: T
authors.lastname: Spruss
authors.forename: Günther
authors.initials: G
authors.lastname: Bernhardt
authors.forename: Armin
authors.initials: A
authors.lastname: Buschauer
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects*; D000166:Acridines / Q000493:pharmacokinetics*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics*; D001921:Brain / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D005434:Flow Cytometry; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000493:pharmacokinetics*; D011804:Quinolines / Q000493:pharmacokinetics*; D044005:Tetrahydroisoquinolines / Q000493:pharmacokinetics*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D011804:Quinolines; D044005:Tetrahydroisoquinolines; C507084:Abcb1b protein, mouse; C402343:tariquidar; C083501:Elacridar; D017239:Paclitaxel