Kinetic and biochemical analysis of carrier-mediated efflux of drugs through the blood-brain and blood-cerebrospinal fluid barriers: importance in the drug delivery to the brain
Y. Sugiyama et al., Kinetic and biochemical analysis of carrier-mediated efflux of drugs through the blood-brain and blood-cerebrospinal fluid barriers: importance in the drug delivery to the brain, J CONTR REL, 62(1-2), 1999, pp. 179-186
In this manuscript, our recent studies on the transporters on the blood-bra
in barrier and blood-cerebrospinal fluid (CSF) barrier responsible for the
excretion of ligands from the central nervous system (CNS) to the blood are
summarized. By comparing the brain entry of quinidine in normal and mdr 1a
knock out mice, the predominant role of P-glycoprotein in the brain distri
bution of this compound was demonstrated. In addition to P-glycoprotein, th
e presence of transporters responsible for the efflux of organic anions fro
m the brain has been suggested by a pharmacokinetic analysis of the CNS dis
tribution of cefodizime, a third generation cephalosporin antibiotic. This
suggestion was confirmed by demonstrating the presence of a specific mechan
ism for the elimination of p-aminohippuric acid from the brain after microi
njection into the cerebral hemisphere. In vitro, the energy-dependent lumin
al preferential efflux of glutathione-bimane was demonstrated in a monolaye
r of MBEC4 cells which were derived from mouse brain endothelial cells. Stu
dies with isolated membrane vesicles from MBEC4 cells suggested the presenc
e of a primary active transporter(s) for organic anions, and Western blot a
nalysis indicated the presence of multidrug resistance associated protein (
MRP1) and/or its related transporters on MBEC4 cells and freshly isolated r
at cerebral endothelial cells. The transcellular transport of 17 beta estra
diol 17 beta-D-glucuronide (E(2)17 beta G) across the choroid plexus was al
so demonstrated by examining the efflux of this compound from CSF after int
racerebroventricular administration. The functional significance of organic
anion transporting polypeptide (oatp-1) on the brush border membrane of th
e choroid plexus was demonstrated by comparing the uptake of E(2)17 beta G
into the isolated choroid plexus and oatp-1 transfected COS-7 cells; in add
ition, reverse transcription-polymerase chain reaction and Western blot ana
lysis indicated the presence of MRP in the choroid plexus. Together with th
e direction of transcellular transport, the basolateral localization of MRP
on the choroid plexus was suggested. By regulating the activity of these e
fflux transporters, it is possible to improve the brain entry of certain su
bstrates. (C) 1999 Elsevier Science B.V. All rights reserved.