Efflux of Taurocholic Acid Across the Blood-Brain Barrier: Interaction with Cyclic Peptides1
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Abstract
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 aKm 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 notp-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 aKm 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.
Footnotes
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Send reprint requests to: Professor, Yuichi Sugiyama, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
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↵1 This work was supported in part by a grant-in-aid from the Ministry of Education, Science, Sports and Culture of Japan, and the Core Research for Evolutional Sciences and Technology of Japan Sciences and Technology Corporation.
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↵2 Current address: Faculty of Pharmaceutical Sciences, Tohoku University, Aramaki azaaoba, Aoba-ku, Sendai, Miyagai 980-77, Japan.
- Abbreviations:
- BBB
- blood-brain barrier
- CNS
- central nervous system
- CSF
- cerebrospinal fluid
- PS product
- permeability-surface area product
- BEI
- brain efflux index
- TC
- taurocholic acid
- CA
- cholic acid
- PAH
- p-aminohippuric acid
- ICG
- indocyanine green
- BSP
- bromosulfophthalein
- TEMA
- tetraethylmethylammonium
- DBSP
- dibromosulfophthalein
- cMOAT
- canalicular multispecific organic anion transporter
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- Received January 22, 1998.
- Accepted April 12, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
