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 [14C]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 [14C]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.
Footnotes
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This project was partially supported by National Institutes of Health Grant CA75466, a grant from Novartis Pharma, and by a fellowship (to H.D.) from the graduate school of University of Nebraska Medical Center.
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DOI: 10.1124/jpet.102.045260
- Abbreviations:
- PDGFR
- platelet-derived growth factor receptor
- CML
- chronic myelogenous leukemia
- CNS
- central nervous system
- MDR1
- multidrug resistance-1 gene
- MDCK
- Madin-Darby canine kidney
- A-to-B
- apical-to-basal
- B-to-A
- basal-to-apical
- HPLC
- high-performance liquid chromatography
- LC-MS
- liquid chromatography-mass spectrometry
- Received October 7, 2002.
- Accepted November 25, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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