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

Takeru Ito; Yoshiyuki Kubo; Yuma Tega; Shin-Ichi Akanuma; Ken-Ichi Hosoya

doi:10.1016/j.xphs.2024.04.020

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

J Pharm Sci. 2024 Apr 26:S0022-3549(24)00149-7. doi: 10.1016/j.xphs.2024.04.020. Online ahead of print.

Authors

Takeru Ito¹, Yoshiyuki Kubo², Yuma Tega¹, Shin-Ichi Akanuma¹, Ken-Ichi Hosoya¹

Affiliations

¹ Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
² 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.

PMID: 38679231
DOI: 10.1016/j.xphs.2024.04.020

Abstract

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 [³H]ribavirin in the testis was 3.6-fold greater than that of [¹⁴C]D-mannitol, a paracellular transport marker, implying transcellular transport of ribavirin across the BTB. Moreover, [³H]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 [³H]ribavirin uptake by TM4 cells at 100 µM. Compared to the uptake of [³H]adenosine, a typical endogenous nucleoside, [³H]ribavirin uptake was relatively similar to ENT2 transport. [³H]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 [³H]ribavirin transport into TM4 cells by 13%. Taken together, these results suggest that ENT2 partially contributes to ribavirin transport at the BTB.

Keywords: Adenosine; Blood–testis barrier (BTB); Equilibrative nucleoside transporter (ENT); Nucleoside transport; Reproductive toxicity; Ribavirin; S-[(4-nitrophenyl)methyl]-6-thioinosine (NBMPR); Sertoli cells; Testis.