title: Acyclovir prodrug for the intestinal di/tri-peptide transporter PEPT1: comparison of in vivo bioavailability in rats and transport in Caco-2 cells.
abstract: It has previously been shown that the prodrug Glu(acyclovir)-Sar has a high affinity for PEPT1 in Caco-2 cells. However, affinity does not necessarily lead to translocation by the transporter which is necessary for achieving an increased oral bioavailability. Therefore i.v. and p.o. doses of Glu(acyclovir)-Sar, acyclovir and valacyclovir were given to rats and the collected blood samples were analysed via LC-MS-MS. Furthermore, Caco-2 cell monolayers were exposed apically to Glu(acyclovir)-Sar, acyclovir, and valacyclovir and the concentration of drug and prodrugs in the cell extracts were determined and taken as a measure for intracellular accumulation. In addition, bi-directional transport studies of Glu(acyclovir)-Sar across Caco-2 cell monolayers and in vitro metabolism studies of Glu(acyclovir)-Sar in various media of rat origin were performed. For these purposes HPLC-UV analysis was applied. Oral administration of Glu(acyclovir)-Sar to rats resulted in low bioavailabilities of acyclovir (<2%) and intact prodrug (<5%). Studies performed on Caco-2 cell monolayers showed that in contrast to valacyclovir Glu(acyclovir)-Sar did not result in a detectable amount of acyclovir or Glu(acyclovir)-Sar in the cell extracts. Bi-directional flux across Caco-2 cell monolayers apical to basolateral (FluxA-->B) and basolateral to apical (FluxB-->A) was measured and the FluxB-->A/FluxA-->B ratios of approximately 0.8 indicate that apical efflux mechanisms may not explain this lack of intracellular accumulation. These data indicate that Glu(acyclovir)-Sar may not be translocated by PEPT1.
authors.affiliation: Molecular Biopharmaceutics, Department of Pharmaceutics, Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Anne Engelbrecht
authors.initials: AE
authors.lastname: Thomsen
authors.forename: Michael Søberg
authors.initials: MS
authors.lastname: Christensen
authors.forename: Morten Aavad
authors.initials: MA
authors.lastname: Bagger
authors.forename: Bente
authors.initials: B
authors.lastname: Steffansen
mesh_terms: D000212:Acyclovir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D018938:Caco-2 Cells; D006801:Humans; D007421:Intestine, Small / Q000378:metabolism*; D008297:Male; D000074011:Peptide Transporter 1; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D027981:Symporters / Q000378:metabolism*
chemical_list: D000074011:Peptide Transporter 1; D011355:Prodrugs; C489940:Slc15a1 protein, rat; D027981:Symporters; D000212:Acyclovir