Han H, de Vrueh R L, Rhie J K, Covitz K M, Smith P L, Lee C P, Oh D M, Sadée W, Amidon G L
College of Pharmacy, University of Michigan, Ann Arbor 48109-1065, USA.
Pharm Res. 1998 Aug;15(8):1154-9. doi: 10.1023/a:1011919319810.
General use of nucleoside analogues in the treatment of viral infections and cancer is often limited by poor oral absorption. Valacyclovir, a water soluble amino acid ester prodrug of acyclovir has been reported to increase the oral bioavailability of acyclovir but its absorption mechanism is unknown. This study characterized the intestinal absorption mechanism of 5' -amino acid ester prodrugs of the antiviral drugs and examined the potential of amino acid esters as an effective strategy for improving oral drug absorption.
Acyclovir (ACV) and Zidovudine (AZT) were selected as the different sugar-modified nucleoside antiviral agents and synthesized to L-valyl esters of ACV and AZT (L-Val-ACV and L-Val-AZT), D-valyl ester of ACV (D-Val-ACV) and glycly ester of ACV (Gly-ACV). The intestinal absorption mechanism of these 5' -amino acid ester prodrugs was characterized in three different experimental systems; in situ rat perfusion model, CHO/hPEPT1 cells and Caco-2 cells.
Testing 5' -amino acid ester prodrugs of acyclovir and AZT, we found that the prodrugs increased the intestinal permeability of the parent nucleoside analogue 3- to 10-fold. The dose- dependent permeation enhancement was selective for L-amino acid esters. Competitive inhibition studies in rats and in CHO cells transfected with the human peptide transporter, hPEPT1, demonstrated that membrane transport of the prodrugs was mediated predominantly by the PEPT1 H+/dipeptide cotransporter even though these prodrugs did not possess a peptide bond. Finally, transport studies in Caco-2 cells confirmed that the 5' - amino acid ester prodrugs enhanced the transcellular transport of the parent drug.
This study demonstrates that L-amino acid-nucleoside chimeras can serve as prodrugs to enhance intestinal absorption via the PEPT1 transporter, providing a novel strategy for improving oral therapy of nucleoside drugs.
核苷类似物在病毒感染和癌症治疗中的广泛应用常常受到口服吸收差的限制。伐昔洛韦是阿昔洛韦的一种水溶性氨基酸酯前药，据报道可提高阿昔洛韦的口服生物利用度，但其吸收机制尚不清楚。本研究对抗病毒药物的5'-氨基酸酯前药的肠道吸收机制进行了表征，并考察了氨基酸酯作为改善口服药物吸收的有效策略的潜力。
选择阿昔洛韦（ACV）和齐多夫定（AZT）作为不同的糖修饰核苷抗病毒剂，并合成了ACV和AZT的L-缬氨酸酯（L-Val-ACV和L-Val-AZT）、ACV的D-缬氨酸酯（D-Val-ACV）和ACV的甘氨酸酯（Gly-ACV）。在三种不同的实验系统中表征了这些5'-氨基酸酯前药的肠道吸收机制；原位大鼠灌注模型、CHO/hPEPT1细胞和Caco-2细胞。
测试阿昔洛韦和AZT的5'-氨基酸酯前药时，我们发现这些前药使母体核苷类似物的肠道通透性提高了3至10倍。剂量依赖性的渗透增强对L-氨基酸酯具有选择性。在大鼠和转染了人肽转运体hPEPT1的CHO细胞中的竞争性抑制研究表明，尽管这些前药不具有肽键，但其膜转运主要由PEPT1 H+/二肽共转运体介导。最后，在Caco-2细胞中的转运研究证实，5'-氨基酸酯前药增强了母体药物的跨细胞转运。
本研究表明，L-氨基酸-核苷嵌合体可作为前药，通过PEPT1转运体增强肠道吸收，为改善核苷类药物的口服治疗提供了一种新策略。
