Tolbutamide Uptake Via pH- and Membrane-potential-dependent Transport Mechanism in Mouse Brain Capillary Endothelial Cell Line

Noriko Koyabu, Hitomi Takanaga, Hirotami Matsuo, Hisakazu Ohtani, Yasufumi Sawada, Mikihiko Naito, Takashi Tsuruo

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Summary: The purpose of this study was to investigate the transport mechanism of tolbutamide across the blood-brain barrier (BBB) using MBEC4 cells as an in vitro BBB model. Methods: The BBB transport of tolbutamide was studied by using a mouse brain capillary endothelial cell line, MBEC4, cultured on dishes with their luminal membrane facing the culture medium. Results: The uptake of [14Cltolbutamide by MBEC4 cells was dependent on temperature and energy. The uptake coefficient of [14C]tolbutamide increased markedly with decreasing pH of the external medium from neutral to acidic. Valinomycin and replacement of chloride with sulfate or gluconate significantly increased the initial uptake of [14C]tolbutamide, while replacement with nitrate significantly decreased it. The uptake was significantly reduced by a proton ionophore, FCCP, and an anion-exchange inhibitor, DIDS. The initial uptake of [14C]tolbutamide was saturable with Kt of 0.61 ± 0.03 mM (pH 7.4) and 1.76±0.19 mM (pH 6.5). At pH 6.5, the initial uptake of [14C]tolbutamide was significantly reduced by several sulfa drugs, salicylic acid, valproic acid and probenecid, and was competitively inhibited by sulfaphenazole (Ki = 3.47 ±0.50 mM) and valproic acid (Ki = 2.29 ±0.43 mM). Conclusion: These observations indicate the existence of a pH-and membrane-potential-dependent anion exchange and/or proton-cotransport system(s) for concentrative uptake of tolbutamide and sulfa drugs in MBEC4 cells.

Original languageEnglish
Pages (from-to)270-279
Number of pages10
JournalDrug Metabolism And Pharmacokinetics
Volume19
Issue number4
DOIs
Publication statusPublished - 2004 Feb 1

Keywords

  • blood-brain barrier
  • brain capillary endothelial cells
  • organic anion

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)

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