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J Pharm Sci. 2019 Sep 11. pii: S0022-3549(19)30570-2. doi: 10.1016/j.xphs.2019.09.005. [Epub ahead of print]

Quantification of ENT1 and ENT2 Proteins at the Placental Barrier and Contribution of These Transporters to Ribavirin Uptake.

Author information

1
Division of Pharmaceutics, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo 105-8512, Japan.
2
Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8577, Japan.
3
Division of Pharmaceutics, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo 105-8512, Japan; Laboratory of Applied Therapeutics, Center for Education and Research on Clinical Pharmacy, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
4
Department of Obstetrics and Gynecology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
5
Division of Pharmaceutics, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo 105-8512, Japan. Electronic address: tomi-ms@pha.keio.ac.jp.

Abstract

The aims of this study are to quantify the protein levels of nucleoside transporters in placental microvillous membranes (MVMs) and to clarify the contributions of these transporters to ribavirin uptake at the placental barrier. Placental MVMs of human and rat expressed equilibrative nucleoside transporter (ENT) 1 protein, whereas the expression of ENT2 protein was obscure. Maternal-to-fetal transfer of [3H]ribavirin in rats was much higher than that of [14C]sucrose. The uptake of [3H]ribavirin by rat placental trophoblast TR-TBT 18 d-1 cells, which functionally express both ENT1 and ENT2 proteins, was saturable, and was significantly inhibited by 0.1 μM nitrobenzylthioinosine, which selectively abolishes ENT1-mediated uptake. Dipyridamole at 10 μM is capable of inhibiting ENT2 as well as ENT1, but a degree of inhibition by 10 μM dipyridamole on [3H]ribavirin uptake was not much different from that by 0.1 μM nitrobenzylthioinosine (ENT1-specific inhibitor). Therefore, ENT2 may contribute little to [3H]ribavirin uptake by these cells. Rat ENT1 cRNA-injected oocytes showed increased [3H]ribavirin uptake compared with water-injected oocytes, while rat ENT2 cRNA-injected oocytes did not. In conclusion, ENT1 protein expressed in placental MVMs appears to play a predominant role in the uptake of ribavirin.

KEYWORDS:

drug transport; membrane transporter(s); nucleoside transporter; pharmacokinetics; placenta; pregnancy

PMID:
31520644
DOI:
10.1016/j.xphs.2019.09.005
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