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Vol. 295, Issue 1, 146-152, October 2000
Faculty of Pharmaceutical Sciences (I.T., J.Y., Y.K., A.O., Y.Sa.,
Y.Sh., K.N., A.T.) Faculty of Medicine (S.K.), Kanazawa University,
Kanazawa, Japan; and Core Research for Evolutional, Science, and
Technology, Japan Science and Technology Corporation,
Moto-machi, Kawaguchi, Japan (I.T., Y.Sa., A.T.)
Transport of new quinolone antibacterial agents (quinolones) at the
blood-brain barrier (BBB) was studied in vitro by using immortalized
rat brain capillary endothelial cells RBEC1, and in vivo by using the
brain perfusion method in rats and multidrug-resistant mdr1a/1b gene-deficient mice. The permeability
coefficient of grepafloxacin measured by brain perfusion was increased
by an excess of unlabeled grepafloxacin, suggesting a participation of
a saturable BBB efflux system. Uptake coefficients of
[14C]grepafloxacin, [14C]sparfloxacin, and
[14C]levofloxacin by RBEC1 cells at the steady state were
increased in the presence of the unlabeled quinolones. The steady-state uptake of [14C]grepafloxacin was increased in the
presence of various quinolones. Brain distributions of
[14C]grepafloxacin and [14C]sparfloxacin
evaluated in terms of the brain-to-plasma free concentration ratio in
mdr1a/1b gene-deficient mice were significantly higher
than those in wild-type mice, demonstrating an involvement of
P-glycoprotein as the efflux transporter. Anionic compounds, including
4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) and
genistein, increased the steady-state uptake of
[14C]grepafloxacin by RBEC1 cells. Because
[14C]grepafloxacin was transported by multidrug
resistance-associated protein (MRP), in MRP1-overexpressing cells and
because RBEC1 and primary cultured brain capillary endothelial cells
expressed MRP1, this protein may be an additional efflux transporter
for quinolones. Furthermore, the permeability coefficient of
[14C]grepafloxacin across the BBB was increased by DIDS
or in the absence of bicarbonate ions in the brain perfusion method.
DIDS or bicarbonate ion did not affect MRP1 function. Accordingly, the
brain distribution of quinolones is restricted by the action of
multiple efflux transporters, including P-glycoprotein, MRP1, and an
unknown anion exchange transporter.
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