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Titolo:
5'-AMINO ACID-ESTERS OF ANTIVIRAL NUCLEOSIDES, ACYCLOVIR, AND AZT AREABSORBED BY THE INTESTINAL PEPT1 PEPTIDE TRANSPORTER
Autore:
HAN HK; DEVRUEH RLA; RHIE JK; COVITZ KMY; SMITH PL; LEE CP; OH DM; SADEE W; AMIDON GL;
Indirizzi:
UNIV MICHIGAN,COLL PHARM ANN ARBOR MI 48109 UNIV MICHIGAN,COLL PHARM ANN ARBOR MI 48109 LEIDEN UNIV,LEIDEN AMSTERDAM CTR DRUG RES,DIV BIOPHARMACEUT LEIDEN NETHERLANDS UNIV CALIF SAN FRANCISCO,DEPT BIOPHARMACEUT SCI & PHARMACEUT CHEM SANFRANCISCO CA 94143 SMITH KLINE BEECHAM PHARMACEUT,DEPT DRUG DELIVERY,PHARMACEUT TECHNOL COLLEGEVILLE PA 19426
Titolo Testata:
Pharmaceutical research
fascicolo: 8, volume: 15, anno: 1998,
pagine: 1154 - 1159
SICI:
0724-8741(1998)15:8<1154:5AOANA>2.0.ZU;2-H
Fonte:
ISI
Lingua:
ENG
Soggetto:
ORAL ABSORPTION; SYSTEM; CARRIER; PHARMACOKINETICS; PRODRUGS; BIOAVAILABILITY; PERMEABILITIES; INHIBITOR; MECHANISM; IMPROVE;
Keywords:
AMINO ACID ESTER; PEPT1 TRANSPORTER; PERMEABILITY; PRODRUGS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
27
Recensione:
Indirizzi per estratti:
Citazione:
H.K. Han et al., "5'-AMINO ACID-ESTERS OF ANTIVIRAL NUCLEOSIDES, ACYCLOVIR, AND AZT AREABSORBED BY THE INTESTINAL PEPT1 PEPTIDE TRANSPORTER", Pharmaceutical research, 15(8), 1998, pp. 1154-1159

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 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 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 situ rat perfusion model, CHO/hPEPT1 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 IO-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, hPEPT1, demonstrated that membrane transport of the prodrugs was mediated predominantly by the PEPT1H+/dipeptide cotransporter even though these prodrugs did not possessa 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 02/07/20 alle ore 21:51:05