DIRECT EVIDENCE FOR PEPTIDE TRANSPORTER (PEPT1)-MEDIATED UPTAKE OF A NONPEPTIDE PRODRUG, VALACYCLOVIR

Xenopus laevis oocytes were used as a gene expression system to charac terize the carrier-mediated transport of valacyclovir (vacv), the L-va line ester prodrug of the acyclic nucleoside acyclovir (acv). A signif icant increase in the uptake of [H-3]vacv by Xenopus laevis oocytes in jected with human intestinal peptide transporter (hPepT1) cRNA compare d to the uptake by water injected oocytes indicated that vacv was tran slocated by hPepT1. Vacv uptake was found to be concentration dependen t, saturable (K-m = 5.94 +/- 1.91 mM and J(max) = 1.68 +/- 0.25 nmoles /hr/oocyte), pH dependent, and inhibited by various known substrates o f hPepT1 but not by acv, valine or pentaglycine. Vacv also inhibited t he uptake of C-14-glycylsarcosine, a known substrate of hPepT1, in a c oncentration-dependent manner (K-i = 4.08 +/- 1.02 mM). These results demonstrate that human intestinal peptide transporter hPepT1 has broad specificity since it recognizes vacv as a substrate even though it la cks a typical peptide bond. (C) 1998 Academic Press.