VALACYCLOVIV - A SUBSTRATE FOR THE INTESTINAL AND RENAL PEPTIDE TRANSPORTERS PEPT1 AND PEPT2

Valacyclovir is a prodrug of the antiviral agent acyclovir and it does not contain a peptide bond in its structure. We studied the interacti on of valacyclovir with the peptide transporters in the human intestin al cell Line Caco-2 and the rat kidney proximal tubular cell line SKPT which differentially express peptide transporters PEPT1 and PEPT2. Th e results of the studies done with these cell lines were confirmed wit h the cloned peptide transporters human PEPT1 and rat PEPT2, expressed heterologously in HeLa cells. The activity of the peptide transporter s was assessed by measuring the uptake of radiolabelled glycylsarcosin e in the presence of a H+ gradient. Valacyclovir inhibited the uptake of glycylsarcosine with an inhibition constant (K-i) of 0.49 +/- 0.04 mM in Caco-2 cells and 0.17 +/- 0.01 mM in SKPT cells. In both cell ty pes, the inhibition was competitive. Acyclovir, in contrast to valacyc lovir, did not interact with the peptide transporters. Similar results were obtained with heterologously expressed human PEPT1 and rat PEPT2 . Valacyclovir inhibited the hPEPT1-mediated glycylsarcosine transport competitively with a Ri value of 0.74 +/- 0.14 mM. The rPEPT2-mediate d transport of glycylsarcosine was also inhibited by valacyclovir comp etitively and the Ri value for the process was 0.39 +/- 0.03 mM. Acycl ovir did not interact with either of these cloned peptide transporters . We conclude that valacyclovir is a substrate for the peptide transpo rters PEPT1 and PEPT2 and that a peptide bond is not a prerequisite fo r recognition as a substrate by the peptide transporters, (C) 1998 Aca demic Press.