Organic anion transporter 3 is involved in the brain-to-blood efflux transport of thiopurine nucleobase analogs

Shinobu Mori, Sumio Ohtsuki, Hitomi Takanaga, Tazuru Kikkawa, Young Sook Kang, Tetsuya Terasaki

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76 Citations (Scopus)


Thiopurines are used as antileukemic drugs. However, during chemotherapy CNS relapses occur due to the proliferation of leukemic cells in the CNS resulting from restricted drug distribution in the brain. The molecular mechanism for this limited cerebral distribution remains unclear. The purpose of this study was to identify the transporter responsible for the brain-to-blood transport of thiopurines across the blood-brain barrier (BBB) using the brain efflux index method. [14C]6-Mercaptopurine (6-MP) and [3H]6-thioguanine were eliminated from rat brain in a time-dependent manner. The elimination of [14C]6-MP was inhibited by substrates of rat organic anion transporters (rOATs), including indomethacin and benzyl-penicillin. rOAT1 and rOAT3 exhibited 6-MP uptake, while benzylpenicillin inhibited rOAT3-mediated uptake, but not that by rOAT1, rOAT3-mediated [14C]6-MP uptake was also inhibited by other thiopurine derivatives. Although methotrexate inhibited rOAT3-mediated [14C]6-MP uptake, the Ki value was 17.5-fold greater than the estimated brain concentration of methotrexate in patients receiving chemotherapy. Accordingly, 6-MP would undergo efflux transport by OAT3 from the brain without any inhibitory effect from coadministered methotrexate in the chemotherapy. In conclusion, rOAT3 is involved in the brain-to-blood transport of thiopurines at the BBB and is one mechanism of limited cerebral distribution.

Original languageEnglish
Pages (from-to)931-941
Number of pages11
JournalJournal of Neurochemistry
Issue number4
Publication statusPublished - 2004 Aug


  • Blood-brain barrier
  • Chemotherapy
  • Efflux transport
  • Organic anion transporter 3
  • Thiopurine

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience


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