Species differences in the pharmacokinetics of cefadroxil as determined in wildtype and humanized PepT1 mice

Abstract

PepT1 (SLC15A1) is a high-capacity low-affinity transporter that is important in the absorption of digested di/tripeptides from dietary protein in the small intestine. PepT1 is also crucial for the intestinal uptake and absorption of therapeutic agents such as the β-lactam aminocephalosporins and antiviral prodrugs. Species differences, however, have been observed in PepT1-mediated intestinal absorption and pharmacokinetics, thereby, making it more difficult to predict systemic drug exposure. In the present study, we evaluated the in situ intestinal permeability of the PepT1 substrate cefadroxil in wildtype and humanized PepT1 (huPepT1) mice, and the in vivo absorption and disposition of drug after escalating oral doses. The in situ perfusions indicated that cefadroxil had a two-fold higher affinity (i.e., two-fold lower Km) for jejunal PepT1 in huPepT1 mice, lower but substantial permeability in all regions of the small intestine, and low but measureable permeability in the colon as compared to wildtype animals. The in vivo experiments indicated almost superimposable pharmacokinetic profiles between the two genotypes after intravenous bolus dosing of cefadroxil. In contrast, after oral dose escalation, the systemic exposure of cefadroxil was reduced in huPepT1 mice as compared to wildtype animals. Moreover, the AUC and Cmax versus dose relationships were nonlinear for huPepT1 but not wildtype mice, and similar to that observed from human subjects. In conclusion, our findings indicate that huPepT1 mice may provide a valuable tool in the drug discovery process by better predicting the oral pharmacokinetic profiles of PepT1 substrates in humans.

Expression and regulation of proton-coupled oligopeptide transporters in colonic tissue and immune cells of mice

“…POTs, which mediate the cellular uptake of di/tripeptides and many peptidomimetics utilizing an inwardly-directed proton gradient and negative membrane potential, are comprised of four mammalian members, namely PEPT1, PEPT2, PHT1 and PHT2. 1, 2 The peptide transporters PEPT1 (considered a low affinity high capacity carrier) and PEPT2 (considered a high affinity low capacity carrier) have broad substrate specificity 3 and, in addition to di/tripeptides, can transport peptide-like drugs such as cefadroxil 4 and valacyclovir 5, 6 . The peptide/histidine transporters PHT1 and PHT2 are unique in their ability to transport histidine in addition to di/tripeptides and some drugs.…”

An Accelerator Mass Spectrometry‐Enabled Microtracer Study to Evaluate the First‐Pass Effect on the Absorption of YH4808

“…The present study also showed that certain genotypes of the CHST3 , SLC15A1 , and SULT1B1 genes were associated with a greater value of F A · F G ( Figure ). The SLC15A1 gene encodes the peptide transporter PepT1, an influx transporter located at the apical side of epithelial cells in the small intestine . Although rs4646227, a variant SNP of the SLC15A1, is considered missense, its clinical impact, particularly on the absorption of a drug, has been rarely studied .…”

In Silico Absorption Analysis of Valacyclovir in Wildtype and Pept1 Knockout Mice Following Oral Dose Escalation

“…Results from this study were particularly noteworthy in delineating the quantitative in vivo contribution of PEPT1 in distinct regions of the small and large intestines, and the significance of luminal hydrolysis in reducing the oral absorption of valacyclovir. Moving forward, a similar analysis should be performed with valacyclovir in other transgenic models such as humanized PEPT1 mice (34) and biphenyl hydrolase-like ( Bphl ) knockout mice. Ultimately, future studies should be aimed at translating these animal models to human in order to better predict a priori oral drug performance, drug-drug interactions, and the development of PEPT1 targeted drugs or prodrugs.…”