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5′-Amino Acid Esters of Antiviral Nucleosides, Acyclovir, and AZT Are Absorbed by the Intestinal PEPT1 Peptide Transporter

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Abstract

Purpose. 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.

Methods. Acyclovir (ACV) and Zidovudine (AZT) were selected as the different sugar-modified nucleo-side 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 glycyl ester of ACV (Gly-ACV). The intestinal absorption mechanism of these 5′-amino acid ester prodrugs was characterized in three different experimental systems; in siturat perfusion model, CHO/hPEPTl cells and Caco-2 cells.

Results. 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 the L-amino acid esters. Competitive inhibition studies in rats and in CHO cells transfected with the human peptide transporter, hPEPTl, 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.

Conclusions. 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.

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Author notes

  1. Julie K. Rhie

    Present address: NIH-NIGMS/FDA-CBER-DCGT, Bethesda, Maryland, 20892

Authors and Affiliations

  1. College of Pharmacy, The University of Michigan, Ann Arbor, Michigan, 48109-1065

    Hyo-kyung Han, Julie K. Rhie, Doo-Man Oh & Gordon L. Amidon1

  2. Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands

    Remco L. A. de Vrueh

  3. Department of Biopharmaceutical Sciences and Pharmaceutical Chemistry, University of California, San Francisco, California

    Kuang-Ming Y. Covitz & Wolfgang Sadee

  4. Department of Drug Delivery, Pharmaceutical Technologies, Smith-Kline Beecham Pharmaceuticals, Collegeville, Pennsylvania, 19426-0989

    Philip L. Smith & Chao-Pin Lee

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  1. Hyo-kyung Han
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  9. Gordon L. Amidon1
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Han, Hk., de Vrueh, R.L.A., Rhie, J.K. et al. 5′-Amino Acid Esters of Antiviral Nucleosides, Acyclovir, and AZT Are Absorbed by the Intestinal PEPT1 Peptide Transporter. Pharm Res 15, 1154–1159 (1998). https://doi.org/10.1023/A:1011919319810

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