Inhibitory Effects of 17-α-Ethinyl-Estradiol and 17-ß-Estradiol on Transport Via the Intestinal Proton-Coupled Amino Acid Transporter (PAT1) Investigated In Vitro and In Vivo.

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-ß-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 IC50 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 (Cmax) of taurine and increased the time (tmax) 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-ß-estradiol were identified as non-translocated and non-competitive inhibitors of PAT1.

Oral and intravenous pharmacokinetics of taurine in sprague-dawley rats: the influence of dose and the possible involvement of the proton-coupled amino acid transporter, PAT1, in oral taurine absorption.

Taurine is involved in various physiological processes, and one of the most abundant amino acids in human. The aim was to investigate the mechanism for intestinal absorption of taurine in vivo using also in vitro mechanistic studies. Taurine absorption was measured in male Sprague-Dawley rats at 10-997 mg/kg and 1-30 mg/kg for oral and intravenous administration, respectively. Oral absorption was measured in the presence of substrates for the proton-coupled amino acid transporter, PAT1, that is, 200 mg/kg proline (Pro) and sarcosine (Sar), and in the presence of 2-Amino-2-norbornanecarboxylic acid (BCH) (200 mg/kg). BCH is not an inhibitor of PAT1 or the taurine transporter, TauT, hence it was included as a negative control. In vitro studies investigating the transport mechanism of taurine were conducted in human intestinal Caco-2 cells. The pharmacokinetic investigations showed that intestinal taurine absorption was not saturable at the investigated doses, but that the time (tmax) to reach the maximal plasma concentration (Cmax) increased with dose. Furthermore, Sar and Pro, but not BCH, decreased taurine Cmax In vitro it was clearly shown that PAT1 mediated the cellular uptake of taurine and thereby facilitated the transepithelial taurine transport, which could be inhibited by Pro and Sar, but not BCH In vivo and in vitro results suggest that taurine absorption from the intestine is caused by PAT1.