In Vitro Interaction of Tetrahydrouridine with Key Human Nucleoside Transporters.

Autor: Säll C; Development ADME, Novo Nordisk A/S, Måløv, Denmark. Electronic address: cxls@novonordisk.com., Koncsos G; SOLVO Biotechnology a Charles River Company, Budapest, Hungary., Klukovits A; SOLVO Biotechnology a Charles River Company, Budapest, Hungary.
Jazyk: angličtina
Zdroj: Journal of pharmaceutical sciences [J Pharm Sci] 2023 Oct; Vol. 112 (10), pp. 2676-2684. Date of Electronic Publication: 2023 Jun 24.
DOI: 10.1016/j.xphs.2023.06.012
Abstrakt: NDec is a novel combination of oral decitabine and tetrahydrouridine that is currently under clinical development for the treatment of sickle cell disease (SCD). Here, we investigate the potential for the tetrahydrouridine component of NDec to act as an inhibitor or substrate of key concentrative nucleoside transporters (CNT1-3) and equilibrative nucleoside transporters (ENT1-2). Nucleoside transporter inhibition and tetrahydrouridine accumulation assays were performed using Madin-Darby canine kidney strain II (MDCKII) cells overexpressing human CNT1, CNT2, CNT3, ENT1, and ENT2 transporters. Results showed that tetrahydrouridine did not influence CNT- or ENT-mediated uridine/adenosine accumulation in MDCKII cells at the concentrations tested (25 and 250 µM). Accumulation of tetrahydrouridine in MDCKII cells was initially shown to be mediated by CNT3 and ENT2. However, while time- and concentration-dependence experiments showed active accumulation of tetrahydrouridine in CNT3-expressing cells, allowing for estimation of K m (3,140 µM) and V max (1,600 pmol/mg protein/min), accumulation of tetrahydrouridine was not observed in ENT2-expressing cells. Potent CNT3 inhibitors are a class of drugs not generally prescribed to patients with SCD, except in certain specific circumstances. These data suggest that NDec can be administered safely with drugs that act as substrates and inhibitors of the nucleoside transporters included in this study.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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