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Vol. 304, Issue 3, 1085-1092, March 2003
Department of Pharmaceutics, University of Minnesota, Minneapolis,
Minnesota (H.D., W.F.E.); Novartis Pharma AG, Preclinical Safety,
Basel, Switzerland (P.M., M.L.); and Novartis Pharma, East Hanover, New
Jersey (M.H.)
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.
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