Inhibitory effects of 17-α-ethinyl-estradiol and 17-β-estradiol on transport via the intestinal proton-coupled amino acid transporter (PAT1) investigated In vitro and in vivo

Carsten Uhd Nielsen*, Maria Pedersen, Stephanie Müller, Thea Kæstel, Maria Bjerg, Nithiya Ulaganathan, Salli Nielsen, Krestine Lundgaard Carlsen, Martha Kampp Nøhr, Rene Holm

*Kontaktforfatter for dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Abstrakt

The proton-coupled amino acid transporter, PAT1, is known to be responsible for intestinal absorption drug substances such as gaboxadol and vigabatrin. The aim of the present study was to investigate, if 17-α-ethinyl-estradiol (E-E2) and 17-β-estradiol (E) inhibit PAT1-mediated intestinal absorption of proline and taurine in vitro in Caco-2 cells and in vivo using Sprague-Dawley rats to assess the potential for taurine-drug interactions. E and E-E2 inhibited the PAT1-mediated uptake of proline and taurine in Caco-2 cells with IC 50 values of 10.0–50.0 μM without major effect on other solute carriers such as the taurine transporter (TauT), di/tri-peptide transporter (PEPT1), and serotonin transporter (SERT1). In PAT1-expressing oocytes E and E-E2 were non-translocated inhibitors. In Caco-2 cells, E and E-E2 lowered the maximal uptake capacity of PAT1 in a non-competitive manner. Likewise, the transepithelial permeability of proline and taurine was reduced in presence of E and E-E2. In male Sprague Dawley rats pre-dosed with E-E2 a decreased maximal plasma concentration (C max) of taurine and increased the time (t max) to reach this was indicated, suggesting the possibility for an in vivo effect on the absorption of PAT1 substrates. In conclusion, 17-α-ethinyl-estradiol and 17-β-estradiol were identified as non-translocated and non-competitive inhibitors of PAT1.

OriginalsprogEngelsk
TidsskriftJournal of Pharmaceutical Sciences
Vol/bind110
Udgave nummer1
Sider (fra-til)354-364
ISSN0022-3549
DOI
StatusUdgivet - jan. 2021

Fingeraftryk Dyk ned i forskningsemnerne om 'Inhibitory effects of 17-α-ethinyl-estradiol and 17-β-estradiol on transport via the intestinal proton-coupled amino acid transporter (PAT1) investigated <i>In vitro and in vivo</i>'. Sammen danner de et unikt fingeraftryk.

Citationsformater