TY - JOUR T1 - Recognition of <span class="sc">l</span>-Amino Acid Ester Compounds by Rat Peptide Transporters PEPT1 and PEPT2 JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 705 LP - 709 VL - 291 IS - 2 AU - Kyoko Sawada AU - Tomohiro Terada AU - Hideyuki Saito AU - Yukiya Hashimoto AU - Ken-Ichi Inui Y1 - 1999/11/01 UR - http://jpet.aspetjournals.org/content/291/2/705.abstract N2 - Peptide transporters (PEPT1 and PEPT2) in epithelia play an important role in the absorption of small peptides and peptide-like drugs. Recently, it was demonstrated that various nonpeptidic compounds can be transported by these transporters. In the present study, we focused on the l-amino acid ester compounds and examined the mechanisms of their interaction with rat PEPTs (rPEPTs) using stable transfectants. Valacyclovir, the l-valyl ester prodrug of the antiherpetic agent acyclovir, competitively inhibited [14C]glycylsarcosine uptake in the rPEPT1- or rPEPT2-expressing cells. Dixon plot analyses showed that the inhibition constant (Ki) values of valacyclovir were 2.7 and 0.22 mM for rPEPT1 and rPEPT2, respectively, suggesting that rPEPT2 had higher affinity for this agent. Various l-valine alkyl esters significantly inhibited [14C]glycylsarcosine uptake. l-Valine methyl ester (Val-OMe) competitively inhibited [14C]glycylsarcosine uptake withKi values of 3.6 and 0.83 mM for rPEPT1 and rPEPT2, respectively, indicating that Val-OMe is also a high-affinity substrate for rPEPT2. Val-OMe had a trans-stimulation effect on [14C]glycylsarcosine efflux from both transfectants, suggesting the translocation of l-valine methyl ester via rPEPTs. Val-OMe showed the most potent inhibitory effect among the several l-amino acid methyl esters examined. We conclude that Val-OMe, as well as valacyclovir, could be recognized and transported by rPEPT1 and rPEPT2 and that thesel-valyl esters showed higher affinity for rPEPT2 as do most substrates of these transporters. Our results suggest thatl-valine is a desirable l-amino acid for the esterification of poorly permeable drugs to enhance their oral bioavailability targeting intestinal PEPT1. The American Society for Pharmacology and Experimental Therapeutics ER -