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Vol. 283, Issue 1, 293-304, 1997
Department of Pharmaceutics, Faculty of Pharmaceutical
Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113, Japan
A distributed model has been used to clarify the mechanism of the
restricted and differential distribution of the quinolone antibiotics
in the rat central nervous system (CNS). The symmetrical permeability
clearances across the blood-brain barrier (BBB), PSBBB, and
across the blood-cerebrospinal fluid barrier (BCSFB), PSCSF, and the active efflux clearances across the BBB,
PSBBB,eff, were obtained from a nonlinear least squares
regression analysis combined with the fast inverse Laplace transforming
program for in vivo data. The values of
PSBBB,eff were 10- to 260-fold greater than those of
PSBBB, providing kinetic evidence to support the hypothesis
that a significant efflux transport across the BBB is responsible for
the limited distribution of quinolones in brain tissue. Moreover, by
simulation studies, we could demonstrate the concentration profiles in
the brain as a function of the distance from the ependymal surface.
However, active efflux transport across the BCSFB has been suggested to
have only a slight effect on the apparent elimination from the
cerebrospinal fluid. Comparing the apparent brain tissue-to-unbound
serum concentration ratio at steady state, it has been suggested that
the net flux across the BBB, i.e., the ratio of
PSBBB to the sum of PSBBB and
PSBBB,eff, is a determinant for the differential
distribution of these quinolones in brain tissue. Such a putative
active efflux transport system would play a significant role in
decreasing the brain interstitial fluid concentration of quinolones.
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