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Vol. 286, Issue 2, 890-895, August 1998
Graduate School of Pharmaceutical Sciences, The University of
Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
The mechanism for the efflux of taurocholic acid (TC) across the
blood-brain barrier (BBB) was studied by examining the elimination of
[3H]TC after microinjection into the cerebral cortex. The
efflux of [3H]TC from the brain was saturable with a
Vmax of 15.0 pmol/min/g brain and a
Km value of 0.396 nmol/0.2 µl injectate.
Efflux was inhibited by cholic acid (CA), a cationic cyclic octapeptide
(octreotide; a somatostatin analogue) and an anionic cyclic
pentapeptide (BQ-123; an endothelin receptor antagonist), with an
IC50 value of 1.09 nmol/0.2 µl injectate, 1.12 nmol/0.2
µl injectate and 0.12 nmol/0.2 µl injectate, respectively.
Probenecid (20 nmol/0.2 µl injectate), but not
p-aminohippuric acid (10 nmol/0.2 µl injectate), inhibited the brain efflux of [3H]TC. In addition, elimination of
[3H]BQ-123 after microinjection was saturable with a
Vmax of 20.8 pmol/min/g brain and a
Km of 2.92 nmol/0.2 µl injectate; it was also
inhibited by TC with an IC50 value of 0.074 nmol/0.2 µl
injectate. In contrast, no significant efflux of
[14C]octreotide from the brain was observed until 60 min
after microinjection. These results suggest that both TC and BQ-123 are
transported from the brain to the circulating blood across the
blood-brain barrier via specific mechanisms. Although mutual inhibition
was observed between TC and BQ-123, kinetic analysis suggested that the
two transport systems differ.
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