5'-AMINO ACID-ESTERS OF ANTIVIRAL NUCLEOSIDES, ACYCLOVIR, AND AZT AREABSORBED BY THE INTESTINAL PEPT1 PEPTIDE TRANSPORTER

Purpose. General use of nucleoside analogues in the treatment of viral infections and cancer is often limited by poor oral absorption. Valac yclovir, a water soluble amino acid ester prodrug of acyclovir has bee n reported to increase the oral bioavailability of acyclovir but its a bsorption mechanism is unknown. This study characterized the intestina l absorption mechanism of 5'-amino acid ester prodrugs of the antivira l drugs and examined the potential of amino acid esters as an effectiv e strategy for improving oral drug absorption. Methods. Acyclovir(ACV) and Zidovudine (AZT) were selected as the different sugar-modified nu cleoside 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 g lycyl ester of ACV (Gly-ACV). The intestinal absorption mechanism of t hese 5'-amino acid ester prodrugs was characterized in three different experimental systems; in situ rat perfusion model, CHO/hPEPT1 cells a nd Caco-2 cells. Results. Testing 5'-amino acid ester prodrugs of acyc lovir and AZT, we found that the prodrugs increased the intestinal per meability of the parent nucleoside analogue 3- to IO-fold. The dose- d ependent permeation enhancement was selective for the L-amino acid est ers. Competitive inhibition studies in rats and in CHO cells transfect ed with the human peptide transporter, hPEPT1, demonstrated that membr ane 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 t hat the 5'-amino acid ester prodrugs enhanced the transcellular transp ort of the parent drug. Conclusions, This study demonstrates that L-am ino acid-nucleoside chimeras can serve as prodrugs to enhance intestin al absorption via the PEPT1 transporter providing a novel strategy for improving oral therapy of nucleoside drugs.