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The purpose of this work was to evaluate the intestinal permeability, oral absorption and disposition of the ester prodrug valacyclovir in wildtype mice and a huPepT1 transgenic mouse model. PepT1 (SLC15A1) is a transporter apically expressed along the lumen of the gastrointestinal tract and is responsible for the absorption of di-/tripeptides, ACE inhibitors, β-lactam antibiotics and numerous prodrugs. Unfortunately, PepT1-mediated substrates that have been extensively studied were shown to exhibit species-dependent absorption and pharmacokinetics. Accordingly, in situ intestinal perfusion studies were conducted and valacyclovir uptake was shown to have a 30-fold lower Km and 100-fold lower Vmax in huPepT1 compared to wildtype mice. Moreover, inhibition studies demonstrated that the huPepT1 transporter alone was responsible for valacyclovir uptake, and segment-dependent studies reported significant reductions in permeability along the length of small intestine in huPepT1 mice. Subsequent oral administration studies revealed that the in vivo rate and extent of valacyclovir absorption were lower in huPepT1 mice, as indicated by 3-fold lower Cmax and 3-fold higher Tmax values, and an AUC0-180 that was 80% of that observed in wildtype mice. However, no significant changes in drug disposition were observed between genotypes after intravenous bolus administration of acyclovir. Lastly, mass balance studies established that the bioavailability of acyclovir, after oral dosing of valacyclovir, was 77.5% in wildtype mice and 52.8% in huPepT1 mice, which corroborated values of 51.3% in clinical studies. Thus, it appears the huPepT1 transgenic mice may be a better model to study prodrug absorption and disposition in humans than wildtype mice.