title: Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux.
abstract: The adequate distribution of STI-571 (Gleevec) to the central nervous system (CNS) is critical for its effective use in CNS tumors. P-glycoprotein-mediated efflux in the blood-brain barrier may play a role in the CNS delivery of this drug. Whether STI-571 is a substrate of P-glycoprotein was determined by examining the directional flux of [(14)C]STI-571 in parental and MDR1-transfected Madin-Darby canine kidney (MDCK) II epithelial cell monolayers. The basolateral-to-apical flux of STI-571 was 39-fold greater than the apical-to-basolateral flux in the MDR1-transfected cells and 8-fold greater in the parental cell monolayers. This difference in directional flux was significantly reduced by a specific P-glycoprotein inhibitor (2R)-anti-5-[3-[4-(10,11-difluoromethanodibenzo-suber-5-yl)piperazin-1-yl]-2-hydroxypropoxy]quinoline trihydrochloride (LY335979). The role of P-glycoprotein in the CNS distribution of STI-571 was examined in vivo, using wild-type and mdr1a/b (-/-) knockout mice that were orally administered 25 mg/kg [(14)C]STI-571. In the wild-type mice, the brain-to-plasma STI-571 concentration ratio at all time points was low (1-3%); however, there was an 11-fold greater brain partitioning of STI-571 at 1 h postdose in the mdr1a/b (-/-) mice compared with the wild-type mice. When 12.5 mg/kg STI-571 was given intravenously, the brain-to-plasma ratio of STI-571 in the mdr1a/b (-/-) mice was approximately 7-fold greater than that of wild-type mice up to 120 min postdose. These data indicate that STI-571 is a substrate of P-glycoprotein, and that the inhibition of P-glycoprotein affects the transport of STI-571 across MDCKII monolayers. Moreover, P-glycoprotein plays an important role in limiting the distribution of STI-571 to the CNS.
authors.affiliation: Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: HaiQing
authors.initials: H
authors.lastname: Dai
authors.forename: Peter
authors.initials: P
authors.lastname: Marbach
authors.forename: Michel
authors.initials: M
authors.lastname: Lemaire
authors.forename: Michael
authors.initials: M
authors.lastname: Hayes
authors.forename: William F
authors.initials: WF
authors.lastname: Elmquist
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D001549:Benzamides; D001692:Biological Transport; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D004285:Dogs; D000068877:Imatinib Mesylate; D051379:Mice; D018345:Mice, Knockout; D010879:Piperazines / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000493:pharmacokinetics*; D014162:Transfection
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate