Increased acyclovir oral bioavailability via a bile acid conjugate

被引:104
作者
Tolle-Sander, Sanna [1 ]
Lentz, Kimberley A. [1 ]
Maeda, Dean Y. [1 ]
Coop, Andrew [1 ]
Polli, James E. [1 ]
机构
[1] Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21202 USA
关键词
prodrug; acyclovir; bioavailability; bile acid;
D O I
10.1021/mp034010t
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 (K-i = 35 mu M), 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 (K-i = 25 mu M). Further characterization showed that acyclovir was catalytically liberated from acyclovir valylchenodeoxycholate 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.
引用
收藏
页码:40 / 48
页数:9
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