Impact of peptide transporter 1 on the intestinal absorption and pharmacokinetics of valacyclovir after oral dose escalation in wild-type and PepT1 knockout mice.
The primary objective of this study was to determine the in vivo absorption properties of valacyclovir, including the potential for saturable proton-coupled oligopeptide transporter 1 (PepT1)-mediated intestinal uptake, after escalating oral doses of prodrug within the clinical dose range. A secondary aim was to characterize the role of PepT1 on the tissue distribution of its active metabolite, acyclovir. [³H]Valacyclovir was administered to wild-type (WT) and PepT1 knockout (KO) mice by oral gavage at doses of 10, 25, 50, and 100 nmol/g. Serial blood samples were collected over 180 minutes, and tissue distribution studies were performed 20 minutes after a 25-nmol/g oral dose of valacyclovir. We found that the C(max) and area under the curve (AUC)₀₋₁₈₀ of acyclovir were 4- to 6-fold and 2- to 3-fold lower, respectively, in KO mice for all four oral doses of valacyclovir. The time to peak concentration of acyclovir was 3- to 10-fold longer in KO compared with WT mice. There was dose proportionality in the C(max) and AUC₀₋₁₈₀ of acyclovir in WT and KO mice over the valacyclovir oral dose range of 10-100 nmol/g (i.e., linear absorption kinetics). No differences were observed in the peripheral tissue distribution of acyclovir once these tissues were adjusted for differences in perfusing drug concentrations in the systemic circulation. In contrast, some differences were observed between genotypes in the concentrations of acyclovir in the distal intestine. Collectively, the findings demonstrate a critical role of intestinal PepT1 in improving the rate and extent of oral absorption for valacyclovir. Moreover, this study provides definitive evidence for the rational development of a PepT1-targeted prodrug strategy.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan.
Bei
B
Yang
Yongjun
Y
Hu
David E
DE
Smith
D000212:Acyclovir / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D007408:Intestinal Absorption / Q000235:genetics / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000074011:Peptide Transporter 1; D027981:Symporters / Q000235:genetics* / Q000378:metabolism*; D014018:Tissue Distribution / Q000235:genetics / Q000502:physiology; D000077483:Valacyclovir; D014633:Valine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D026901:Membrane Transport Proteins; D000074011:Peptide Transporter 1; C489941:Slc15a1 protein, mouse; D027981:Symporters; C067802:intestinal peptide-proton cotransporter; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir