Efflux of taurocholic acid across the blood-brain barrier: interaction with cyclic peptides.
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 microl 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 microl injectate, 1.12 nmol/0.2 microl injectate and 0.12 nmol/0.2 microl injectate, respectively. Probenecid (20 nmol/0.2 microl injectate), but not p-aminohippuric acid (10 nmol/0.2 microl 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 microl injectate; it was also inhibited by TC with an IC50 value of 0.074 nmol/0.2 microl 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.
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
T
T
Kitazawa
T
T
Terasaki
H
H
Suzuki
A
A
Kakee
Y
Y
Sugiyama
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002756:Cholagogues and Choleretics / Q000493:pharmacokinetics*; D019826:Cholic Acid; D002793:Cholic Acids / Q000494:pharmacology; D006728:Hormones / Q000494:pharmacology; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D008845:Microinjections; D015282:Octreotide / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D013656:Taurocholic Acid / Q000493:pharmacokinetics*; D013997:Time Factors
D002756:Cholagogues and Choleretics; D002793:Cholic Acids; D006728:Hormones; D008024:Ligands; D010456:Peptides, Cyclic; D013656:Taurocholic Acid; D019826:Cholic Acid; D015282:Octreotide; C072247:cyclo(Trp-Asp-Pro-Val-Leu)