Abstract

Sartans are very effective drugs for treatment of hypertension, heart failure, and other cardiovascular disorders. They antagonize the effects of angiotensin II at the AT₁ receptor and display p.o. bioavailability rates of 13 to 80%. Because some sartans sterically resemble dipeptide derivatives, we investigated whether they are transported by peptide transporters. We first assessed the effects of sartans on [¹⁴C]glycylsarcosine uptake into Caco-2 cells expressing H⁺/peptide transporter (PEPT) 1 and into SKPT cells expressing PEPT2. Losartan, irbesartan, valsartan, and eprosartan inhibited [glycine-1-¹⁴C]glycylsarcosine ([¹⁴C]Gly-Sar) uptake into Caco-2 cells in a competitive manner with K_i values of 24, 230, 390, and >1000 μM. Losartan and valsartan also strongly inhibited the total transepithelial flux of [¹⁴C]Gly-Sar across Caco-2 cell monolayers. In SKPT cells, [¹⁴C]Gly-Sar uptake was inhibited with K_i values of 2.2 μM (losartan), 65 μM (irbesartan), 260 μM (valsartan), and 490 μM (eprosartan). We determined by the two-electrode voltage-clamp technique whether the compounds elicited transport currents by PEPT1 or PEPT2 when expressed in Xenopus laevis oocytes. No currents were observed for any of the sartans, but the compounds strongly and reversibly inhibited peptide-induced currents. Uptake of valsartan, losartan, and cefadroxil was quantified in HeLa cells after heterologous expression of human PEPT1 (hPEPT1). In contrast to cefadroxil, no PEPT1-specific uptake of valsartan and losartan was found. We conclude that the sartans tested in this study display high-affinity interaction with PEPTs but are not transported themselves. However, they strongly inhibit hPEPT1-mediated uptake of dipeptides and cefadroxil.