title: Increased acyclovir oral bioavailability via a bile acid conjugate.
abstract: The objective of this work was to design an acyclovir prodrug that would utilize the human apical sodium-dependent bile acid transporter (hASBT) and enhance acyclovir oral bioavailability. Using each chenodeoxycholate, deoxycholate, cholate, and ursodeoxycholate, four bile acid prodrugs of acyclovir were synthesized, where acyclovir was conjugated to a bile acid via a valine linker. The affinity of the prodrug for hASBT was determined through inhibition of taurocholate uptake by COS-7 cells transfected with hASBT (hASBT-COS). The prodrug with the highest inhibitory affinity was further evaluated in vitro and in vivo. The prodrug acyclovir valylchenodeoxycholate yielded the highest affinity for hASBT (Ki = 35 microM), showing that chenodeoxycholate is the free bile acid with the greatest affinity for hASBT. Acyclovir valylchenodeoxycholate's affinity was similar to that of cholic acid (Ki = 25 microM). Further characterization showed that acyclovir was catalytically liberated from acyclovir valylchenode-oxycholate by esterase. Relative to cellular uptake studies of acyclovir alone, the cellular uptake from the prodrug resulted in a 16-fold greater acyclovir accumulation within hASBT-COS cells, indicating enhanced permeation properties of the prodrug. Enhanced permeability was due to hASBT-mediated uptake and increased passive permeability. The extent of acyclovir uptake in the presence of sodium was 1.4-fold greater than the extent of passive prodrug uptake in the absence of sodium (p = 0.02), indicating translocation of the prodrug by hASBT. The prodrug also exhibited an almost 12-fold enhanced passive permeability, relative to acyclovir's passive permeability. Oral administration of acyclovir valylchenodeoxycholate to rats resulted in a 2-fold increase in the bioavailability of acyclovir, compared to the bioavailability after administration of acyclovir alone. Results indicate that a bile acid prodrug strategy may be useful in improving the oral bioavailability of intestinal permeability-limited compounds.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21202, USA.
authors.forename: Sanna
authors.initials: S
authors.lastname: Tolle-Sander
authors.forename: Kimberley A
authors.initials: KA
authors.lastname: Lentz
authors.forename: Dean Y
authors.initials: DY
authors.lastname: Maeda
authors.forename: Andrew
authors.initials: A
authors.lastname: Coop
authors.forename: James E
authors.initials: JE
authors.lastname: Polli
mesh_terms: D000212:Acyclovir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001647:Bile Acids and Salts / Q000493:pharmacokinetics*; D001682:Biological Availability; D001692:Biological Transport; D019556:COS Cells; D002635:Chenodeoxycholic Acid / Q000493:pharmacokinetics; D002522:Chlorocebus aethiops; D007700:Kinetics; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics
chemical_list: D000998:Antiviral Agents; D001647:Bile Acids and Salts; D011355:Prodrugs; D002635:Chenodeoxycholic Acid; D000212:Acyclovir