Significance of Peptide Transporter 1 in the Intestinal Permeability of Valacyclovir in Wild-Type and PepT1 Knockout Mice

The purpose of this study was to quantitatively determine the contribution of PepT1 [peptide transporter 1 (SLC15A1)] to the intestinal permeability of valacyclovir, an ester prodrug of the antiviral drug acyclovir. In situ single-pass intestinal perfusions were employed (pH 6.5 x 90 minutes) to assess the effective permeability (P-eff) of 100 mu M [H-3] valacyclovir in wild-type and PepT1 knockout mice. Acyclovir pharmacokinetics was also evaluated after oral administration of 25 nmol/g valacyclovir. In wild-type mice, jejunal uptake of valacyclovir was best described by both saturable (K-m = 10.2 mM) and nonsaturable components where the saturable pathway accounted for 82% of total transport. Valacyclovir P-eff was 2.4 x 10(-4) cm/s in duodenum, 1.7 x 10(-4) cm/s in jejunum, 2.1 x 10(-4) cm/s in ileum, and 0.27 x 10(-4) cm/s in colon. In Pept1 knockout mice, P-eff values were about 10% of that in wild-type animals for these small intestinal segments. Valacyclovir P-eff was similar in the colon of both genotypes. There were no differences in valacyclovir P-eff between any of the intestinal segments of PepT1 knockout mice. Valacyclovir P-eff was significantly reduced by the dipeptide glycylsarcosine and the aminocephalosporin cefadroxil, but not by the amino acids L-valine or L-histidine, the organic acid p-aminohippurate, or the organic base tetraethylammonium (all at 25 mM). PepT1 ablation resulted in 3- to 5-fold reductions in the in vivo rate and extent of valacyclovir absorption. Our findings conclusively demonstrate, using in situ and in vivo validations in genetically modified mice, that PepT1 has a major influence in improving the oral absorption of valacyclovir.