Increased acyclovir oral bioavailability via a bile acid conjugate

Area of Science:

• Drug Delivery and Pharmaceutical Sciences
• Biochemistry and Molecular Biology
• Gastroenterology

Background:

• Acyclovir has poor oral bioavailability due to limited intestinal permeability.
• Bile acid transporters, such as the human apical sodium-dependent bile acid transporter (hASBT), are potential targets for improving drug absorption.
• Prodrug strategies can be employed to enhance the delivery and efficacy of existing drugs.

Purpose of the Study:

• To design and synthesize acyclovir prodrugs conjugated with different bile acids.
• To evaluate the affinity of these prodrugs for the hASBT.
• To assess the in vitro and in vivo performance of the most promising prodrug for enhanced acyclovir oral bioavailability.

Main Methods:

• Synthesis of four acyclovir-bile acid conjugate prodrugs via a valine linker.
• Determination of hASBT affinity using inhibition of taurocholate uptake in hASBT-transfected cells.
• In vitro characterization including cellular uptake and passive permeability studies.
• In vivo oral administration to rats to measure acyclovir bioavailability.

Main Results:

• Acyclovir valylchenodeoxycholate exhibited the highest affinity for hASBT (Ki = 35 µM).
• The prodrug demonstrated a 16-fold increase in cellular acyclovir accumulation and a 12-fold enhanced passive permeability compared to acyclovir alone.
• Oral administration in rats resulted in a 2-fold increase in acyclovir bioavailability.

Conclusions:

• Bile acid conjugation via a valine linker is an effective strategy to create acyclovir prodrugs.
• Acyclovir valylchenodeoxycholate leverages hASBT-mediated uptake and enhanced passive permeability for improved drug delivery.
• This bile acid prodrug approach shows promise for enhancing the oral bioavailability of drugs with poor intestinal permeability.