Objective: Proton-coupled peptide transporters, expressed in intestine, kidney, choroid plexus and other tissues, mediate the uptake of dipeptides and several peptidomimetic derivatives into epithelial cells (Brandsch 2009). In many articles and almost every review on peptide transporters it is claimed that PEPT1 mediates the intestinal absorption of ACE inhibitors thereby allowing their oral administration. Methods and Results: We systematically investigated the interaction of ACE inhibitors with human PEPT1 and PEPT2 expressed constitutively or heterologously in several epithelial mammalian cell lines. For most ACE inhibitors, medium or low affinity was found. In H⁺ /peptide symporter-expressing Xenopus laevis oocytes, very low currents were recorded by the two-electrode voltage clamp technique only for lisinopril, enalapril, quinapril and benazepril at hPEPT1 and for spirapril at hPEPT2. For the other ACE inhibitors electrogenic transport was not significant or not measurable at all. The situation is similar for antihypertensives of the sartan type. Losartan, irbesartan, valsartan and eprosartan interact with hPEPT1 and hPEPT2 with high affinity. However, in hPEPT1- or hPEPT2-expressing X. laevis oocytes, no currents were observed for any of the sartans. The sartans, on the other hand, strongly and reversibly inhibited peptide-induced currents. In heterologously transfected HeLa cells, hPEPT1-specific uptake of cefadroxil but not of valsartan and losartan was found. Conclusion: Our results suggest that in contrast to current views, proton-coupled peptide transporters do not control intestinal absorption and renal reabsorption of ACE inhibitors. Sartans strongly inhibit the PEPT1-mediated uptake of cefadroxil and dipeptides. Further studies are needed to show whether these inhibitor-substrate interactions found in vitro affect peptide absorption or drug pharmacokinetics also in vivo. Brandsch, M. 2009. Expert Opin Drug Metab Toxicol 5, 887-905