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

Authors
Mori, SOhtsuki, STakanaga, HKikkawa, TKang, YSTerasaki, T
Issue Date
Aug-2004
Publisher
WILEY
Keywords
blood-brain barrier; chemotherapy; efflux transport; organic anion transporter 3; thiopurine
Citation
JOURNAL OF NEUROCHEMISTRY, v.90, no.4, pp 931 - 941
Pages
11
Journal Title
JOURNAL OF NEUROCHEMISTRY
Volume
90
Number
4
Start Page
931
End Page
941
URI
https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/15850
DOI
10.1111/j.1471-4159.2004.02552.x
ISSN
0022-3042
1471-4159
Abstract
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. [C-14]6-Mercaptopurine (6-MP) and [H-3]6-thioguanine were eliminated from rat brain in a time-dependent manner. The elimination of [C-14]6-MP was inhibited by substrates of rat organic anion transporters (rOATs), including indomethacin and benzylpenicillin. rOAT1 and rOAT3 exhibited 6-MP uptake, while benzylpenicillin inhibited rOAT3-mediated uptake, but not that by rOAT1. rOAT3-mediated [C-14]6-MP uptake was also inhibited by other thiopurine derivatives. Although methotrexate inhibited rOAT3-mediated [C-14]6-MP uptake, the K-i 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.
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