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Characterization of the Mechanism of Zidovudine Uptake by Rat Conditionally Immortalized Syncytiotrophoblast Cell Line TR-TBT

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Abstract

Purpose

To characterize the uptake mechanism of zidovudine (AZT), a nucleoside reverse transcriptase inhibitor, in syncytiotrophoblast cells using the TR-TBT 18d-1 cell line previously established by our group.

Materials and Methods

The effects of several transporter inhibitors on the initial and steady-state apical uptake of AZT by TR-TBT 18d-1 were characterized, in order to identify the transporter(s) involved.

Results

Initial uptake of AZT was sodium-independent and saturable; the K m value was about 16 μM. Nitrobenzylthioinosine (NBMPR), probenecid and cimetidine each had little effect on the saturable AZT uptake, indicating that well characterized transporters, such as organic anion transporters (OATs and OATPs), organic cation transporters (OCTs) and equilibrative nucleoside transporters (ENTs), are not involved. However, thymidine and 2′-deoxyuridine strongly inhibited AZT uptake. These results suggest that an unidentified nucleoside uptake transporter is responsible for the uptake of AZT. Cyclosporin A, Ko143 and probenecid had little effect on AZT accumulation by TR-TBT 18d-1 cells, suggesting that transporter-mediated efflux of AZT is not substantial.

Conclusion

Our results indicate that saturable AZT uptake into TR-TBT 18d-1 is mediated by a so-far-unidentified transporter.

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Abbreviations

AZT:

3′-azido-3′-deoxythymidine

BCRP:

breast cancer resistance protein

CNT:

concentrative nucleoside transporter

DHEAS:

dehydroepiandrosterone sulfate

ENT:

equilibrative nucleoside transporter

MRP:

multidrug resistance protein

NMBPR:

nitrobenzylthioinosine

OAT:

organic anion transporter

OATP:

organic anion transporting polypeptide

OCT:

organic cation transporter

PAH:

-aminohippuric acid

P-gp:

p-glycoprotein

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Acknowledgement

This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, a grant from the “High-Tech Research Center” and “Open Research Center” Project for Private Universities matching fund subsidy, the Science Research Promotion Fund from the Promotion and Mutual Aid Corporation for Private Schools of Japan, and a grant from the Joint Research Project under the Japan-Korea Basic Scientific Cooperation Program of the Japan Society for the Promotion of Science (JSPS) and Korea Science & Engineering Foundation (KOSEF), and the SRC program (R 11-2005-017) of the KOSEF/MOST.

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Authors and Affiliations

  1. Department of Pharmaceutics, Kyoritsu University of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan

    Y. Sai, T. Nishimura, S. Shimpo, T. Chishu, K. Sato, N. Kose & E. Nakashima

  2. Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Japan

    T. Terasaki

  3. SORST, Japan Science and Technology Agency (JST), Kawaguchi, 332-0012, Japan

    T. Terasaki

  4. Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan

    C. Mukai, S. Kitagaki & N. Miyakoshi

  5. College of Pharmacy, Sookmyung Women’s University, Seoul, 140-742, Korea

    Y.-S. Kang

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  1. Y. Sai
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  2. T. Nishimura
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Correspondence to Y. Sai.

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Sai, Y., Nishimura, T., Shimpo, S. et al. Characterization of the Mechanism of Zidovudine Uptake by Rat Conditionally Immortalized Syncytiotrophoblast Cell Line TR-TBT. Pharm Res 25, 1647–1653 (2008). https://doi.org/10.1007/s11095-008-9564-9

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  • DOI: https://doi.org/10.1007/s11095-008-9564-9

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