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

Abstract

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 3 90 minutes) to assess the effective permeability (P eff ) of 100 mM [ 3 H]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 3 10 24 cm/s in duodenum, 1.7 3 10 24 cm/s in jejunum, 2.1 3 10 24 cm/s in ileum, and 0.27 3 10 24 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.

PepT1 expressed in immune cells has an important role in promoting the immune response during experimentally induced colitis

“…In the present study, we used PepT1-KO mice, [51][52][53][54] in which PepT1 is not expressed in colonic epithelial or immune cells, and WT mice, in which PepT1 is expressed in immune cells but not in colonic epithelial cells. First, we observed that DSS-induced colitis was less severe in PepT1-KO mice compare with WT mice.…”

In situ perfusion in rodents to explore intestinal drug absorption: Challenges and opportunities

“…The expression of OATP2B1, the most 655 predominant OATP isoenzyme in human small intestine, has been 656 observed to be higher in the ileum than in the duodenum, although 657 this difference was not statistically significant (Meier et al, 2007). 658 Similarly, the rat isoenzymes Oatp2b1 and Oatp1a5 exhibit higher (Jappar et al, 2010;Yang and Smith, 2013). In wild type mice, in situ 742 permeability for these compounds was observed to be significantly 743 lower in the colon compared to permeability in the small intestine.…”

A Minireview: Usefulness of Transporter-Targeted Prodrugs in Enhancing Membrane Permeability

“…50 The impact of PepT1 on the intestinal absorption of valacyclovir was confirmed by using PepT1 knockout (KO) mice, in which Cmax and area under the concentration-time curve (AUC) of ACV after oral administration of valacyclovir were 4-to 6-fold and 2-to 3-fold lower in KO mice, respectively, as compared with those in wildtype mice. 51,52 The usefulness of dipeptide ester prodrugs of ACV was also examined using Val-Val, Gly-Val, Gly-Gly, Gly-Tyr, Val-Try, and Tyr-Val ester moieties. 25 All dipeptide prodrugs except Try-Gly-ACV exhibited a higher affinity toward PEPT1 than cephalexin, a typical substrate for PEPT1, and the affinity and permeability across Caco-2 cell membrane of Gly-Val-ACV was comparable with those of Val-ACV.…”