Blood-to-Testis Transport of Ribavirin Involves Carrier-Mediated Processes at the Blood-Testis Barrier.

Autor: Ito T; Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan., Kubo Y; Laboratory of Drug Disposition & Pharmacokinetics, Faculty of Pharmaceutical Sciences, Teikyo University, Kaga 2-11-1, Tokyo 173-8605, Japan. Electronic address: kubo.yoshiyuki.jf@teikyo-u.ac.jp., Tega Y; Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan., Akanuma SI; Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan., Hosoya KI; Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
Jazyk: angličtina
Zdroj: Journal of pharmaceutical sciences [J Pharm Sci] 2024 Aug; Vol. 113 (8), pp. 2616-2624. Date of Electronic Publication: 2024 Apr 26.
DOI: 10.1016/j.xphs.2024.04.020
Abstrakt: Ribavirin, an antiretroviral agent targeting the hepatitis C virus, causes male reproductive toxicity. This study investigated the mechanism of ribavirin transport at the blood-testis barrier (BTB). In vivo mouse integration plot analysis after intravenous administration revealed that the net influx clearance of [ 3 H]ribavirin in the testis was 3.6-fold greater than that of [ 14 C]D-mannitol, a paracellular transport marker, implying transcellular transport of ribavirin across the BTB. Moreover, [ 3 H]ribavirin uptake by TM4 cells, mouse-derived Sertoli cells, was time- and concentration-dependent, with a K m value of 2.49 mM. S-[(4-nitrophenyl)methyl]-6-thioinosine, an inhibitor of Na + -independent equilibrative nucleoside transporters (ENTs), strongly inhibited the [ 3 H]ribavirin uptake by TM4 cells at 100 µM. Compared to the uptake of [ 3 H]adenosine, a typical endogenous nucleoside, [ 3 H]ribavirin uptake was relatively similar to ENT2 transport. [ 3 H]Ribavirin uptake was also observed in mouse ENT2-expressing Xenopus laevis oocytes, and gene silencing via the transfection of ENT2 small interfering RNA significantly reduced the [ 3 H]ribavirin transport into TM4 cells by 13%. Taken together, these results suggest that ENT2 partially contributes to ribavirin transport at the BTB.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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