Received for publication July 9, 2008.
Revised August 15, 2008.
Accepted for publication August 18, 2008.

Transport of Angiotensin-converting Enzyme Inhibitors by H⁺/Peptide Transporters Revisited

Abstract

Angiotensin-converting enzyme (ACE) inhibitors are often regarded as substrates for the peptide transporters PEPT1 and PEPT2. Even though the conclusions drawn from published data are quite inconsistent, in most review articles PEPT1 is claimed to mediate the intestinal absorption of ACE inhibitors and thus to determine their oral availability. We systematically investigated the interaction of a series of ACE inhibitors with PEPT1 and PEPT2. First, we studied the effect of fourteen ACE inhibitors including new drugs on the uptake of the dipeptide [¹⁴C]Gly-Sar into human intestinal Caco-2 cells constitutively expressing PEPT1 and rat renal SKPT cells expressing PEPT2. In a second approach, the interaction of ACE inhibitors with heterologously expressed human PEPT1 and PEPT2 was determined. In both assay systems, zofenopril and fosinopril were found to have very high affinity for binding to peptide transporters. Medium to low affinity for transporter interaction was found for benazepril, quinapril, trandolapril, spirapril, cilazapril, ramipril, moexipril, quinaprilat and perindopril. For enalapril, lisinopril and captopril very weak affinity or lack of interaction was found. Transport currents of PEPT1 and PEPT2 expressed in Xenopus laevis oocytes were recorded by the two-electrode voltage clamp technique. Statistically significant, but very low currents were only observed for lisinopril, enalapril, quinapril and benazepril at PEPT1 and for spirapril at PEPT2. For the other ACE inhibitors electrogenic transport activity was extremely low or not measurable at all. The present results suggest that peptide transporters do not control intestinal absorption and renal reabsorption of ACE-inhibitors.

Key words: ACE inhibitors, Drug Delivery, Xenopus laevis oocytes, intestine, membrane transport, peptide transport